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PubMed2026

Glycemic and Renal Effects of SGLT2 Inhibitors in Monogenic Diabetes: A Real-World National Study.

AIMS: Evidence regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in monogenic diabetes is limited. We evaluated real-world metabolic, renal, and safety outcomes of SGLT2i therapy in adults with monogenic diabetes. MATERIALS AND METHODS: This multicenter retrospective study included adults with genetically confirmed monogenic diabetes treated with SGLT2i. Clinical and biological data were collected at baseline and after approximately 1 and 2 years. Longitudinal changes were analysed using linear mixed-effects models adjusted for baseline value, age, and sex and treatment intensification. RESULTS: Forty patients (mean age 48.6 ± 15.2 years) with MIDD (n = 16), HNF1B-MODY (n = 9), HNF1A/HNF4A-MODY (n = 11), or other MODY subtypes (ABCC8, INS, RFX6; n = 4) were followed for 23.9 ± 5.9 months. HbA1c remained stable overall but decreased significantly in patients with baseline HbA1c ≥ 8% (9.6% ± 1.3% to 7.6% ± 0.7%; p = 0.001). UACR declined significantly (-35.6% at 1 year and -43.5% at 2 years; p = 0.004), particularly in those with baseline CKD (trend). Genotype-specific trends suggested greater glycemic improvement in HNF1A/HNF4A-MODY and greater UACR reduction in MIDD. eGFR declined modestly over time. Non-serious adverse events occurred in 15% of patients, 7.5% discontinued treatment, and no ketoacidosis, acute kidney injury, or deaths were reported. CONCLUSIONS: In this nationwide cohort of patients with monogenic diabetes-the largest reported to date-SGLT2i therapy was associated with improved glycemic control in individuals with baseline HbA1c ≥ 8%, reduced albuminuria, and showed a favourable safety profile. These findings support SGLT2i as a potential therapeutic option that warrants confirmation in larger controlled studies.

Humans↗

PubMed2026

Metabolic Stress Testing Reveals Persistent Lipid-Handling Dysfunction in Women With Polycystic Ovary Syndrome Despite Exercise Training.

AIM: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and metabolic dysfunction, yet baseline metabolomic studies show inconsistent findings. We investigated whether metabolic abnormalities in PCOS emerge under physiological stress and how these responses are modified by exercise training. MATERIALS AND METHODS: Twelve women with PCOS and 10 controls completed hyperinsulinaemic-euglycaemic clamps with randomised saline or lipid infusion, before and after 8 weeks of supervised exercise. Plasma metabolomics (163 metabolites) were measured at baseline, post-infusion and post-clamp. Linear mixed-effects models assessed Group × Timepoint × Intervention interactions. RESULTS: No baseline metabolite differences were observed between groups. A significant three-way interaction (p = 0.008) indicated condition-dependent trajectory divergence. Post hoc analysis revealed a specific divergence during post-exercise lipid challenge (p = 0.048). Women with PCOS showed reduced suppression of ether-linked phosphatidylcholines during insulin-stimulated lipid loading (PC ae C44:4, p = 0.031), despite exercise-induced improvements in fitness and normalisation of amino acid profiles. Exploratory metabolite ratios suggested impaired substrate coordination under stress. CONCLUSIONS: Metabolic defects in PCOS are stress-dependent and not detectable at rest. Exercise training improves resting metabolism but reveals persistent impairment in adaptive lipid handling during combined insulin and lipid challenges, suggesting impaired coordination of substrate supply during metabolic stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ISRCTN42448814.

Humans↗

PubMed2004

A practical approach to a multi-level analysis with a sparse binary outcome within a large surgical trial.

OBJECTIVES: To assess the potential source of variation that surgeon may add to patient outcome in a clinical trial of surgical procedures. METHODS: Two large (n = 1380) parallel multicentre randomized surgical trials were undertaken to compare laparoscopically assisted hysterectomy with conventional methods of abdominal and vaginal hysterectomy; involving 43 surgeons. The primary end point of the trial was the occurrence of at least one major complication. Patients were nested within surgeons giving the data set a hierarchical structure. A total of 10% of patients had at least one major complication, that is, a sparse binary outcome variable. A linear mixed logistic regression model (with logit link function) was used to model the probability of a major complication, with surgeon fitted as a random effect. Models were fitted using the method of maximum likelihood in SAS. RESULTS: There were many convergence problems. These were resolved using a variety of approaches including; treating all effects as fixed for the initial model building; modelling the variance of a parameter on a logarithmic scale and centering of continuous covariates. The initial model building process indicated no significant 'type of operation' across surgeon interaction effect in either trial, the 'type of operation' term was highly significant in the abdominal trial, and the 'surgeon' term was not significant in either trial. CONCLUSIONS: The analysis did not find a surgeon effect but it is difficult to conclude that there was not a difference between surgeons. The statistical test may have lacked sufficient power, the variance estimates were small with large standard errors, indicating that the precision of the variance estimates may be questionable.

Humans↗

PubMed2006

Prevalence of sleep problems and their association with inattention/hyperactivity among children aged 6-15 in Taiwan.

This study investigated the 6-month prevalence rates of sleep-related problems and their association with daytime inadvertent napping, inattention, hyperactivity/impulsivity, and oppositional symptoms in children and adolescents. A representative school-based sample of 2463 first to ninth graders was recruited using a multistage sampling method. The instruments included the Sleep Habits Questionnaire (including dyssomnia, parasomnia, sleep schedules, and sleep-disordered breathing), the Chinese Health Questionnaire, and the Chinese versions of the Conners' Parent and Teacher Rating Scales-Revised: Short forms. The informants were mothers and teachers. The linear and nonlinear mixed models were used for statistical analyses and sex and age were controlled in the model. Results showed that the rates of middle insomnia, disturbed circadian rhythm, mouth breathing, and daytime inadvertent napping increased with age; whereas those of bedwetting, bruxism, sleep terrors decreased with age. Dyssomnia, sleep-disordered breathing problems, daytime inadvertent napping, and sleep schedules were related to attention-deficit/hyperactivity disorder (ADHD)-related symptoms as assessed by mothers' and teachers' ratings. Parasomnia was associated with ADHD-related symptoms as assessed by mothers' ratings. Our findings suggest an age trend of sleep problems similar to those found in the literature and the association of daytime inadvertent napping, inattention, hyperactivity/impulsivity, and oppositional symptoms with sleep-related problems.

Adolescent↗

PubMed2006

Circadian change of cardiac autonomic function in correlation with intra-esophageal pH.

BACKGROUND AND AIM: Although autonomic alterations are observed in patients with gastroesophageal reflux disease (GERD), the influence of visceral receptor responses on the dynamics of autonomic function remains unknown. The aim of this study was to investigate the autonomic functional changes in association with intra-esophageal pH under ambulation. METHODS: Thirty patients referred for 48 h ambulatory pH monitoring underwent simultaneous 24 h cardiac monitoring for heart rate variability (HRV). We used linear mixed-effects models to estimate the relationship between esophageal acid exposure and power spectral analysis of HRV, including low-frequency power (0.04 < LF < 0.15 Hz), high-frequency power (0.15 < or = HF < 0.4 Hz), and LF/HF power ratio. RESULTS: Over the 24-h period, patients with pathological reflux had lower average LF and HF powers than patients with functional heartburn, but the LF/HF power ratios were similar for the two patient groups. As we stratified the data according to waking and sleeping times, a significantly higher HF power but lower LF/HF power ratio was found during sleeping time regardless of diagnosis. In the regression analysis, esophageal pH was positively associated with change (not basal tone) of both LF and HF powers during waking, but only with change of HF power during sleeping time. The significant associations between pH values and changes in HRV decreased gradually with time. The LF/HF power ratio did not alter significantly with pH. CONCLUSION: Esophageal acid exposure is generally associated with decreases in autonomic tone. A predominant parasympathetic fluctuation during sleeping and a superimposed sympathetic interaction during waking dictate diurnal characteristics of autonomic regulation.

Adult↗

PubMed2006

Flexible modeling via a hybrid estimation scheme in generalized mixed models for longitudinal data.

To circumvent the computational complexity of likelihood inference in generalized mixed models that assume linear or more general additive regression models of covariate effects, Laplace's approximations to multiple integrals in the likelihood have been commonly used without addressing the issue of adequacy of the approximations for individuals with sparse observations. In this article, we propose a hybrid estimation scheme to address this issue. The likelihoods for subjects with sparse observations use Monte Carlo approximations involving importance sampling, while Laplace's approximation is used for the likelihoods of other subjects that satisfy a certain diagnostic check on the adequacy of Laplace's approximation. Because of its computational tractability, the proposed approach allows flexible modeling of covariate effects by using regression splines and model selection procedures for knot and variable selection. Its computational and statistical advantages are illustrated by simulation and by application to longitudinal data from a fecundity study of fruit flies, for which overdispersion is modeled via a double exponential family.

Animals↗

PubMed2004

Pharmacokinetics of pegylated recombinant human megakaryocyte growth and development factor in healthy volunteers and patients with hematological disorders.

OBJECTIVES: The purpose of this study is to examine the pharmacokinetics of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in healthy volunteers with normal hematopoiesis and patients with idiopathic thrombocytopenic purpura (ITP), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and aplastic anemia (AA). METHODS: PEG-rHuMGDF was intravenously administered to healthy volunteers and patients with ITP, AML, MDS, and AA. The serum concentration of PEG-rHuMGDF was measured and the pharmacokinetics was investigated using non-linear mixed-effects modeling technique. RESULTS: The systemic clearance (CL) and volume of distribution at steady-state (Vss) consistently decreased in the healthy subjects, when the dose increased. In AML patients, CL and Vss decreased when the dose increased, but the change of CL was not statistically significant. In contrast, no significant dose dependency of these parameter estimates was observed in MDS patients. In AA patients there was no significant change in Vss but the CL of the higher dose groups was slightly smaller than that of the lower dose groups. Relatively smaller CL and Vss in ITP patients than those of healthy volunteers at the same dose were observed. CONCLUSIONS: This saturable pathway of CL may involve the receptor-mediated endocytosis and degradation by megakaryocyte lineage cells and platelets. The saturable distribution space can be also explained by the receptors on hematopoietic cells. The non-saturable distribution space corresponds to the value of plasma and interstitial fluid volume.

Case-Control Studies↗

PubMed2006

Interactions of serum albumin, valproic acid and carbamazepine with the pharmacokinetics of phenytoin in cancer patients.

Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was <1 mg/l on 132 occasions (51.2%) and >2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P<0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.

Administration, Oral↗

PubMed1997

A comparison of the standard approach and the NONMEM approach in the estimation of bioavailability in man.

There has recently been concern about confidence intervals calculated using the standard error of parameter estimates from NONMEM, a computer program that uses a non-linear mixed-effects model to calculate relative bioavailability (F), because of possible downward bias of these estimates. In this study an alternate approach, the log-likelihood procedure, was used to calculate the confidence intervals for F from NONMEM. These were then compared with those calculated using the standard error of the parameter estimates, the traditional NONMEM approach, and the standard model-independent method, to determine whether bias exists. By use of data from a single dose, open cross-over study of ibuprofen using 14 healthy male volunteers, NONMEM was shown to give results consistent with those obtained using the standard model-independent method of analysis and could be a useful tool in the determination of F where conditions for using the standard method of analysis are not optimum. The width of the confidence interval for F using the log-likelihood procedure was narrower and non-symmetrical when compared with that obtained using the traditional NONMEM approach. The width of the confidence interval obtained using the traditional NONMEM method was similar to that from the standard approach, however the parameter estimate for F was higher than that obtained from the standard method. This could have been because of an outlier in the data set to which the standard approach is more sensitive. No downward bias was found in the confidence intervals from NONMEM. The bioavailability data set was of relatively low variability and more research with highly variable data is necessary before it can be concluded that the confidence intervals calculated from NONMEM can be used for hypothesis testing.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Tobacco use in popular movies during the past decade.

OBJECTIVE: The top 50 commercially successful films released per year from 1991 to 2000 were content coded to assess trends in tobacco use over time and attributes of films predictive of higher smoking rates. DESIGN: This observational study used media content analysis methods to generate data about tobacco use depictions in films studied (n = 497). Films are the basic unit of analysis. Once films were coded and preliminary analysis completed, outcome data were transformed to approximate multivariate normality before being analysed with general linear models and longitudinal mixed method regression methods. MAIN OUTCOME MEASURES: Tobacco use per minute of film was the main outcome measure used. Predictor variables include attributes of films and actors. Tobacco use was defined as any cigarette, cigar, and chewing tobacco use as well as the display of smoke and cigarette paraphernalia such as ashtrays, brand names, or logos within frames of films reviewed. RESULTS: Smoking rates in the top films fluctuated yearly over the decade with an overall modest downward trend (p < 0.005), with the exception of R rated films where rates went up. CONCLUSIONS: The decrease in smoking rates found in films in the past decade is modest given extensive efforts to educate the entertainment industry on this issue over the past decade. Monitoring, education, advocacy, and policy change to bring tobacco depiction rates down further should continue.

Age Factors↗

PubMed2004

Tumor volume in pharyngolaryngeal squamous cell carcinoma: comparison at CT, MR imaging, and FDG PET and validation with surgical specimen.

PURPOSE: To compare computed tomography (CT), magnetic resonance (MR) imaging, and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for delineation of gross tumor volume (GTV) in pharyngolaryngeal squamous cell carcinoma and to validate results with the macroscopic surgical specimen when available. MATERIALS AND METHODS: Twenty-nine patients with stages II-IV squamous cell carcinoma treated with radiation therapy or chemotherapy and radiation therapy (n = 20) or with total laryngectomy (n = 9) were enrolled. Ten patients had oropharyngeal, 13 had laryngeal, and six had hypopharyngeal tumors. CT, MR imaging, and PET were performed with patients immobilized in a customized thermoplastic mask, and images were coregistered. GTVs obtained with the three modalities were compared quantitatively and qualitatively. If patients underwent total laryngectomy, images were validated with the surgical specimen after three-dimensional coregistration. The effect of each modality was estimated with linear mixed-effects models. Adjustments for multiple comparisons were made with the Bonferonni or Sidak method. RESULTS: For oropharyngeal tumors and for laryngeal or hypopharyngeal tumors, no significant difference (P >.99) was observed between average GTVs delineated at CT (32.0 and 21.4 cm(3), respectively) or MR imaging (27.9 and 21.4 cm(3), respectively), whereas average GTVs at PET were smaller (20.3 [P </=.10] and 16.4 cm(3) [P </=.01], respectively). GTVs from surgical specimens were significantly smaller (12.6 cm(3), P </=.06). In nine patients for whom a surgical specimen was available, no modality adequately depicted superficial tumor extension; this was due to limitations in spatial resolution. In addition, false-positive results were seen for cartilage, extralaryngeal, and preepiglottic extensions. CONCLUSION: Compared with GTVs at CT and MR imaging, GTVs at FDG PET were smaller. In nine patients for whom a surgical specimen was available, PET was found to be the most accurate modality. However, no modality managed to depict superficial tumor extension.

Adult↗

PubMed2006

Early emphysematous changes in asymptomatic smokers: detection with 3He MR imaging.

PURPOSE: To prospectively compare apparent diffusion coefficient (ADC) measurements derived from diffusion-weighted hyperpolarized helium 3 (3He) magnetic resonance (MR) imaging with functional and structural findings using spirometric tests and thin-section computed tomography (CT) of the lungs in asymptomatic smokers and healthy nonsmokers of similar age. MATERIALS AND METHODS: All studies were HIPAA compliant and were approved by the institutional review board. Informed consent was obtained. Ventilation and diffusion-weighted 3He MR images were obtained in healthy subjects: 11 smokers (five women, six men; mean age, 47 years+/-18 [standard deviation]; range, 23-73 years) and eight nonsmokers (<100 cigarettes in lifetime) (four women, four men; mean age, 46 years+/-16; range, 23-69 years). Mean ADC values for smokers and nonsmokers were compared with spirometric values, diffusing capacity of the lung for carbon monoxide (Dlco), age, and pack-years with Spearman rank correlation coefficient (rs) and multiple linear regression analysis. Mean ADC value and thin-section CT emphysema index of relative area less than -950 HU (RA950) were compared on a regional basis by using linear mixed-effect models. RESULTS: Mean ADC values and number of pack-years were significantly correlated (rs=0.60; 95% confidence interval (CI): 0.21, 1.00; P=.007); relationship remained significant after adjustment for age (P=.003). Dlco was strongly correlated with pack-years (rs=-0.63; 95% CI: -0.97, -0.29; P=.004). Negative correlations between mean ADC values and percentage predicted Dlco (rs=-0.79; 95% CI: -0.93, -0.64; P<.001) and the ratio of forced expiratory volume in 1 second to forced vital capacity (rs=-0.72; 95% CI: -0.92, -0.52; P=.001) were statistically significant. Correlations between spirometric values or RA950 and number of pack-years were not significant (.05 level). CONCLUSION: Correlations between mean ADC values and pulmonary function test measurements for diagnosing emphysema, especially Dlco, were statistically significant.

Adolescent↗

PubMed2005

apoE4 allele and the natural history of cardiovascular risk factors.

The aims of the present study were to compare the longitudinal changes in traditional cardiovascular (CV) risk factors (blood pressure, BMI, total and HDL-cholesterol, triglycerides, and blood glucose) in men with and without the apolipoprotein (apo)E4 allele. Three hundred six men from the Baltimore Longitudinal Study of Aging, ranging in age from 20 to 92 yr, were studied. Repeated measurements of CV risk factors were performed over a median follow-up time of 7 yr (maximum 14.3 yr) for men. Longitudinal changes in these CV risk factors were analyzed by linear mixed-effects models. The prevalence of the apoE4 allele was 25.5%. apoE4 was independently associated with accelerated changes over time in fasting plasma glucose (+9.5% vs. no change in those without apoE4 in the 6th age-decade over 10 yr). No significant effect of apoE4 on longitudinal changes in total or HDL-cholesterol, triglycerides, or blood pressures was observed. In conclusion, apoE4 influences fasting plasma glucose and its changes over time. This could explain, in part, the increased CV risk associated with the apoE4 genotype observed in men.

Adult↗

PubMed2005

Variation of C-reactive protein levels in adolescents: association with sleep-disordered breathing and sleep duration.

BACKGROUND: There is increasing evidence that sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular disease (CVD) in adults. C-reactive protein (CRP), a marker of systemic inflammation, is an important predictor of future cardiovascular events. The goal of this study was to quantify the associations of SDB, sleep duration, and CRP in adolescents to better understand the role of SDB in CVD risk. METHODS AND RESULTS: Adolescents (n=143; age, 13 to 18 years; 36% black; 50% female) with a wide range of SDB severity underwent polysomnography and measurement of high-sensitivity CRP. SDB was quantified with the apnea hypopnea index (AHI) and oxygen desaturation measures. Sleep duration was estimated from 7-day actigraphy. The independent and dose-response associations of SDB with CRP were addressed through linear mixed-effects models. Forty-eight percent were overweight or obese, and 12% had SDB (AHI > or =5). CRP levels varied with increasing body mass index and SDB. After adjustment for body mass index , age, sex, and race, mean CRP levels were 0.50, 0.43, 0.97, and 1.66 mg/L for SDB severity levels of AHI <1, 1 to 4.9, 5 to 14.9, and > or =15, respectively (P=0.0049, AHI > or =15 versus <1). Adjusted mean CRP levels demonstrated a dose response with SDB above a threshold AHI of 5. This association was partially explained by overnight hypoxemia and less so by sleep duration. CONCLUSIONS: In adolescents free of known CVD, an AHI > or =5 is associated with increasing levels of CRP, suggesting that pediatric SDB may confer additional CVD risk beyond that of obesity.

Adolescent↗

PubMed2004

Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project.

BACKGROUND AND PURPOSE: Low blood pressure has been related to an increased risk of dementia. We sought to verify blood pressure variations before and after a dementia diagnosis and to relate blood pressure decline to subsequent Alzheimer disease and dementia. METHODS: A community dementia-free cohort aged > or =75 years (n=947) underwent follow-up examinations twice over a period of 6 years to detect dementia cases (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised [DSM-III-R] criteria, n=304). Blood pressure variation before and after dementia diagnosis was verified with linear mixed-effects models. Using the dementia-free cohort identified at first follow-up (n=719), the association between blood pressure decline from baseline to first follow-up and subsequent risk of dementia was examined. RESULTS: Blood pressure markedly decreased over 3 years before dementia diagnosis and afterward, whereas no substantial decline was present 3 to 6 years before the diagnosis. However, among subjects with baseline systolic pressure <160 mm Hg, systolic pressure decline > or =15 mm Hg occurring 3 to 6 years before diagnosis was associated with relative risks (95% CI) of 3.1 (1.3 to 7.0) for Alzheimer disease and 3.1 (1.5 to 6.3) for dementia. There was a dose-response relationship between systolic pressure decline and dementia risk in subjects with vascular disease. CONCLUSIONS: Blood pressure starts to decrease only 3 years before dementia diagnosis and continues to decline afterward. A greater decline in systolic pressure occurring 3 to 6 years before diagnosis is associated with an increased risk of dementia only in older people with already low blood pressure or affected by vascular disorders.

Aged↗

PubMed2005

Outcomes and associated risk factors for aortic valve replacement in 160 children: a competing-risks analysis.

BACKGROUND: We sought to define patient characteristics, outcomes, and associated risk factors after aortic valve replacement (AVR) in children. METHODS AND RESULTS: Clinical records from children undergoing AVR from 1974 to 2004 at our institution were reviewed. Competing-risks methodology determined the time-related prevalence of 3 mutually exclusive end states: death, repeated replacement, and survival without subsequent AVR and their associated risk factors. Longitudinal echocardiographic data were analyzed by mixed linear-regression models. Children (n=160) underwent 198 AVRs, with 33 having >1. Competing-risks analysis predicted that 10 years from the initial AVR, 19% had died without subsequent AVR, 34% underwent a second AVR, and 47% remained alive without replacement. Risk factors for death without a second AVR included lower weight (P<0.001) and younger age at AVR (P=0.04), performance of aortic arch reconstruction together with AVR (P=0.03), and nonautograft use (P=0.03). Risk factors for a second AVR included earlier operation year (P=0.04) and implantation of a bioprosthetic or homograft valve (P=0.004). Analysis of serial echocardiographic measurements showed that pulmonary autograft use was associated with slower progression of peak aortic gradient (P=0.002), smaller left ventricular dimension (P=0.04), and decreased prevalence of aortic regurgitation (P=0.04). CONCLUSIONS: Mortality and repeated valve replacement are common after initial AVR in children, especially in younger patients and those with bioprosthetic or homograft valves. Pulmonary autograft use is associated with decreased mortality, slower gradient progression, and smaller left ventricular dimension.

Adolescent↗

PubMed2026

Plasma von Willebrand Factor and ADAMTS13 Interact With APOE-ε4 in Predicting Longitudinal Brain Atrophy and Cognitive Decline Over a 9-Year Follow-Up.

BACKGROUND: Von Willebrand factor (VWF) and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) are linked to dementia risk, and limited evidence suggests apolipoprotein E (APOE)-ε4 alters VWF release. This study assessed whether baseline VWF and ADAMTS13 levels predict neurodegeneration and cognitive decline and evaluated effect modification by APOE-ε4 carriership. METHODS: Vanderbilt Memory and Aging Project cohort participants (n=332, 73±7 years, 59% male) completed serial blood draw, neuropsychological assessment, and brain magnetic resonance imaging over 6.4 years (range 1.4-9.7 years). Baseline plasma VWF and ADAMTS13 levels were quantified using mass spectrometry and Olink. Fully adjusted linear mixed-effects models related protein×time and protein×APOE-ε4×time interaction terms to longitudinal brain magnetic resonance imaging and neuropsychological outcomes. RESULTS: Lower baseline ADAMTS13 predicted faster declines in language (β=0.11, P=0.01), information processing speed (β=0.27, P=0.001), executive function (β=0.01, P=0.03), episodic memory (β=0.01, P=0.03), and visuospatial ability (β=0.11, P=0.001) and faster increases in global (β=-0.29, P=0.01) and frontal (β=-0.17, P=0.01) white matter hyperintensity volumes. Associations between ADAMTS13 and faster rates of cognitive decline and white matter injury were driven by APOE-ε4 carriers. Models relating VWF to longitudinal outcomes were null. APOE-ε4 interacted with VWF on longitudinal gray matter volumetric outcomes, such that faster rates of global gray matter atrophy were observed with higher baseline VWF levels among APOE-ε4 noncarriers only (β=-1530.5, P<0.001). CONCLUSIONS: ADAMTS13 shows promise as a potential plasma biomarker for brain aging outcomes, but additional research is warranted to understand the performance of VWF in the presence versus absence of an APOE-ε4 allele.

Humans↗

PubMed2006

Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis.

RATIONALE: The relationship between sensitization to Aspergillus fumigatus and progression of pulmonary function is not yet established in cystic fibrosis (CF). OBJECTIVES: We aimed to evaluate onset of A. fumigatus sensitization and development of allergic bronchopulmonary aspergillosis (ABPA), as well as to determine the physiologic factors of lung function influencing these mechanisms in CF. METHODS: Serial annual lung function tests performed in 122 children with CF (62 males; 60 females; age: 6-18 yr) provided data pertaining to FRC measured by plethysmography, lung clearance index, volume of trapped gas, effective specific airway resistance, and forced expiratory indices (FEV1, FEF at 50% VC). Specific IgE to recombinant A. fumigatus allergens, rAspf1 and rAspf3, served as marker for sensitization, and to rAspf4 and rAspf6 as indications for a serologic ABPA, were clinically diagnosed (Nelson criteria). By linear mixed-effect model analysis, five patient groups, (1) not sensitized and free from Pseudomonas aeruginosa, (2) intermittently P. aeruginosa colonized, (3) chronically P. aeruginosa infected, (4) sensitized, and (5) with ABPA, were retrospectively evaluated. MEASUREMENTS AND MAIN RESULTS: A. fumigatus sensitization was best reflected by increased rAspf1+3-specific IgE levels, whereas, in most patients, sensitization was preceded by P. aeruginosa infection. Patients with ABPA demonstrated the most severe progression in all lung function parameters, and FEF at 50% VC, volume of trapped gas, and effective specific airway resistance were the best predictors (p < 0.0001). However, regarding distinction between sensitization to A. fumigatus and development of ABPA in the course of CF, chronic P. aeruginosa infection has to be taken into account. CONCLUSIONS: Airway narrowing, gas trapping, and small airway disease are the major targets for functional derangement in ABPA.

Adolescent↗