Routine Clinical Measurements Research Articles

Abstract P102: Reducing Testing Burden in Patients Screened for Primary Aldosteronism

Introduction: Primary aldosteronism (PA) is an increasingly recognized secondary cause of hypertension characterized by higher cardiovascular, renal, and metabolic disease rates than blood pressure-matched essential hypertensives. Current literature suggests expanding screening for PA to include the majority, if not all, hypertensive patients. This expansive screening would place considerable burden on patients and the healthcare system. A simple clinical risk prediction model that identifies patients with low risk for PA could reduce this testing burden. Methods: We evaluated 111 hypertensive patients in the Southern Illinois University Hypertension Clinic who underwent a screening test and, if positive, had subsequent confirmatory testing for PA. We characterized patients based on routine clinical measures including antihypertensive treatment intensity, blood pressure, serum electrolytes, and body size. Classification trees incorporating 96 patients without missing data points for any considered predictor variable were used to identify hypertensive screen-positive patients who have low to absent risk for PA as determined by confirmatory testing. Results: Patients with PA had higher serum aldosterone levels at screening (mean = 22.5 ng/dl ± SD = 11.6 vs. 15.2 ± 4.5, p < 0.001), higher BMI (35.8 kg/m 2 ± 9.9 vs. 29.9 ± 5.8, p < 0.001), lower potassium (3.9 mmol/L ± 0.5 vs. 4.1 ± 0.6, p = 0.03), and more intense antihypertensive drug therapy (defined by the World Health Organization defined daily dose [6.1 ± 3.2 vs. 4.4 ± 3.0, p = 0.01]) than hypertensive patients without PA. The optimal classification tree model performed relatively poorly at differentiating those with PA from those without PA (sensitivity = 0.76, specificity = 0.86, positive predictive value = 0.87, and negative predictive value = 0.73). However, the model did reveal a subset of individuals who consistently tested negative for PA. Out of 14 patients with serum aldosterone concentration < 25.5, serum potassium > 3.55, and BMI < 27, none had PA. Conclusion: We identified a set of readily available clinical variables for identifying hypertensive patients who screened positive for PA but in whom PA was subsequently proven to be absent. Applying these criteria to our screen-positive hypertensive cohort reduces confirmatory testing by approximately 15%. Study in a larger sample size and external validation of this model is needed prior to recommending it for use in clinical decision-making.

The use of accelerometer bracelets to evaluate arm motor function over a stroke rehabilitation period – an explorative observational study

BackgroundAssessments of arm motor function are usually based on clinical examinations or self-reported rating scales. Wrist-worn accelerometers can be a good complement to measure movement patterns after stroke. Currently there is limited knowledge of how accelerometry correlate to clinically used scales. The purpose of this study was therefore to evaluate the relationship between intermittent measurements of wrist-worn accelerometers and the patient’s progression of arm motor function assessed by routine clinical outcome measures during a rehabilitation period.MethodsPatients enrolled in in-hospital rehabilitation following a stroke were invited. Included patients were asked to wear wrist accelerometers for 24 h at the start (T1) and end (T2) of their rehabilitation period. On both occasions arm motor function was assessed by the modified Motor Assessment Scale (M_MAS) and the Motor Activity Log (MAL). The recorded accelerometry was compared to M_MAS and MAL.Results20 patients were included, of which 18 completed all measurements and were therefore included in the final analysis. The resulting Spearman’s rank correlation coefficient showed a strong positive correlation between measured wrist acceleration in the affected arm and M-MAS and MAL values at T1, 0.94 (p < 0.05) for M_MAS and 0.74 (p < 0.05) for the MAL values, and a slightly weaker positive correlation at T2, 0.57 (p < 0.05) for M_MAS and 0.46 − 0.45 (p = 0.06) for the MAL values. However, no correlation was seen for the difference between the two sessions.ConclusionsThe results confirm that the wrist acceleration can differentiate between the affected and non-affected arm, and that there is a positive correlation between accelerometry and clinical measures. Many of the patients did not change their M-MAS or MAL scores during the rehabilitation period, which may explain why no correlation was seen for the difference between measurements during the rehabilitation period. Further studies should include continuous accelerometry throughout the rehabilitation period to reduce the impact of day-to-day variability.

Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study.

With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.75 ng/mL) after >3 years' (median 74 months) diabetes duration. Models included clinical measures at the baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL cholesterol), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS). Models using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with C-peptide ≥0.75 ng/mL (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under the receiver operating characteristic curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope 0.995-0.999). Models retained high performance for predicting retained C-peptide in older youth with obesity (AUCROC 0.88-0.96) and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92). Prediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with T2D.

Predictors of clinical outcome in adults with repaired tetralogy of Fallot and the prognostic value of surrogate markers of right ventricular dyssynchrony

Abstract Introduction Sequelae or residual lesions after surgical repair of tetralogy of Fallot (rTOF) are inevitable and have an impact on long-term outcome. So far, most of our attention was directed to negative consequences of residual pulmonary regurgitation. Less attention has been paid to the impact of right bundle branch block and intraventricular dyssynchrony on biventricular function, exercise capacity and clinical outcome. Purpose Using the Swiss Adult Congenital HEart disease Registry we aimed to investigate the 5-year clinical course of adults with rTOF late after surgical repair. We used echocardiography strain analysis as surrogate to quantify right and left ventricular dyssynchrony and correlated our findings with routine clinical measures from cardiopulmonary exercise testing, neurohumoral blood work and cardiac magnetic resonance imaging with the aim to identify patients at increased risk for an adverse clinical event. Methods 2D speckle-tracking strain analysis of the right and left ventricle was performed with dedicated software (Tomtec, Germany). RV dyssynchrony index was measured as the standard deviation of time to peak shortening (TTP) in six RV segments. Interventricular shortening delay (IVSD) was defined as the maximal delay of TTP between ventricular segments. We constructed a multivariate model with NT-proBNP, ECG, clinical, imaging and exercise testing variables to predict the composite outcome of all-cause mortality, relevant arrhythmias and hospital admission for decompensated heart failure. Results A total of 285 patients were included. During a mean follow-up of 48±21 months, 33 patient (12 %) suffered an adverse event with a mean time to event of 30 ± 21 months after the baseline visit. RV dyssynchrony index and IVSD did not differ statistically between the groups with and without events (49±31ms vs 41±18ms, p-value 0.21, 130±65ms vs. 103±50ms, p-value 0.9). In the multivariate Cox-regression model, NT-proBNP, right atrial area and peak heart rate at exercise testing were independent predictors of outcome. An integrated risk score with the median values of these 3 variables as cut-off was highly accurate in separating patients at low risk (score 0; n=39) and high risk (score 3; n=38) for an adverse event. After 6 years of follow-up, no patient at low risk (score 0) had an adverse event, while in 62% of patients at high risk (score 3) an adverse event occurred (p&amp;lt;0.001). Conclusion In our cohort of rTOF patients, echocardiographic surrogates of RV dyssynchrony did not correlate with clinical events. An integrated multimodality approach proved to be effective in predicting outcomes.

Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study.

Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention "success" (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme. We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life. Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out. In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.

Precision gestational diabetes treatment: a systematic review and meta-analyses

BackgroundGestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus.MethodsWe conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions.ResultsThere was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis.ConclusionsClinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.

Radiographic Technique for Routine Clinical Measurement of Postoperative Total Knee Extension

Introduction: We propose a novel clinical technique to easily obtain a radiographic measurement for terminal passive knee extension based upon a weight-bearing lateral radiograph. Materials and Methods: Lateral radiographs were obtained with the patient in the standing position. The leg was positioned with slight hip flexion and full passive extension of the knee by instructing the patient to bear partial weight through their heel, with simultaneous use of a wooden wedge to dorsiflex the foot to neutral and to aid in balance. A Terminal extension was measured radiographically with digital imaging software. Fifty postoperative knee radiographs were used in assessing inter-observer and intra-observer reliability. Results: Inter-observer reliability yielded an Intraclass Correlation Coefficient of 0.973. The correlation coefficient for intra-observer reliability was 0.980. Conclusion: With the use of weight-bearing extension radiographs and our measurement technique, we present a method that can easily be applied across any setting in total knee arthroplasty to obtain accurate, objective data on patient knee extension.

Neonatal Depression Is Associated With 1-Year Mortality in Critical Congenital Heart Disease.

Background Low 5-minute Apgar scores (AS) are predictive of term and preterm neonatal mortality but have not been well studied in the critical congenital heart disease (CCHD) population. We analyzed US national vital statistics data to evaluate the association between neonatal depression (AS 0-3) and 1-year mortality in CCHD. Methods and Results We performed a retrospective cohort study using 2014 to 2018 Centers for Disease Control and Prevention cohort-linked birth certificate and infant death records. Five-minute AS were categorized as ≤3, 4 to 6, or ≥7. We calculated birth rates and associated mortality rates by AS group in infants with and without CCHD. Multivariable logistic regression analyzed neonatal, maternal, and pregnancy-related risk factors for neonatal depression and 1-year mortality. Of 11 642 neonates with CCHD (0.06% of all births), the 5.8% with AS 0 to 3 accounted for 23.3% of all 1-year CCHD mortality, with 69.9% of deaths occurring within 1 month of life. Gestational age at birth, growth restriction, extracardiac defects, race, and low maternal education were associated with an increased odds of AS 0 to 3 in neonates with CCHD relative to those with AS 7 to 10 on multivariable analysis. AS 0 to 3 was associated with 1-year CCHD mortality after adjusting for these factors, prenatal care, and delivery location (adjusted odds ratio, 14.57 [95% CI, 11.73-18.10]). Conclusions The AS is a routine clinical measure providing important prognostic information in CCHD. These findings suggest that prenatal and perinatal factors, beyond those included in current risk stratification tools, are important for CCHD outcomes. Multidisciplinary collaboration to understand the pathophysiology underlying neonatal depression may help identify interventions to improve CCHD mortality rates.

Cholesterol Contributes to Risk, Severity, and Machine Learning-Driven Diagnosis of Lyme Disease.

Lyme disease is the most prevalent vector-borne disease in the US, yet its host factors are poorly understood and diagnostic tests are limited. We evaluated patients in a large health system to uncover cholesterol's role in the susceptibility, severity, and machine learning-based diagnosis of Lyme disease. A longitudinal health system cohort comprised 1 019 175 individuals with electronic health record data and 50 329 with linked genetic data. Associations of blood cholesterol level, cholesterol genetic scores comprising common genetic variants, and burden of rare loss-of-function (LoF) variants in cholesterol metabolism genes with Lyme disease were investigated. A portable machine learning model was constructed and tested to predict Lyme disease using routine lipid and clinical measurements. There were 3832 cases of Lyme disease. Increasing cholesterol was associated with greater risk of Lyme disease and hypercholesterolemia was more prevalent in Lyme disease cases than in controls. Cholesterol genetic scores and rare LoF variants in CD36 and LDLR were associated with Lyme disease risk. Serological profiling of cases revealed parallel trajectories of rising cholesterol and immunoglobulin levels over the disease course, including marked increases in individuals with LoF variants and high cholesterol genetic scores. The machine learning model predicted Lyme disease solely using routine lipid panel, blood count, and metabolic measurements. These results demonstrate the value of large-scale genetic and clinical data to reveal host factors underlying infectious disease biology, risk, and prognosis and the potential for their clinical translation to machine learning diagnostics that do not need specialized assays.

Prospective assessment of nighttime respiratory disturbance in multiple myeloma patients

Chronic intermittent hypoxia, a feature of sleep apnea, is a potent driver of solid tumor cancers and promotes lethal engraftment of malignant plasma cells in a mouse model. The objective of this study was to investigate if nighttime respiratory disturbances affect clinical outcomes in a multiple myeloma patient population. To do so, we prospectively assessed nighttime respiratory disturbance index (RDI) in 44 patients (27 male, 17 female) diagnosed with multiple myeloma at the University of Iowa Hospitals and Clinics. Following this assessment, we categorized patients by RDI and utilized electronic medical records to explore differences in routine myeloma clinical measures. We found 93% of the patients had an RDI equal to clinical sleep apnea. 39% of patients had a moderate or severe RDI. In comparing these patients to those with low RDI, there were no statistical differences in any clinical performance indicator. Additionally, there were no differences in disease symptoms, multiple myeloma staging, or antibody type between these groups. However, patients with a higher nighttime RDI were less likely to respond to induction chemotherapy (p=0.046), a predictor of poor disease prognosis. These data support the hypothesis that nighttime respiratory disturbances negatively impact multiple myeloma patients, but this impact may not be evident in routine clinical tests of patient performance. This research is supported by NIH award R01CA244271 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bone density and trabecular bone score to predict fractures in adults aged 20-39years: a registry-based study.

Trabecular bone score (TBS), a bone texture measurement, is associated with fracture risk independent of bone mineral density (BMD) in older adults. In adults aged 20-40years, TBS remains stable and its role in fracture risk assessment is unclear. We utilized the Manitoba Bone Density Registry to explore the relationship of fracture risk with BMD and TBS in younger adults. Women and men aged 20-39years referred for DXA testing were studied. Incident major and any fractures were captured from health records. Categories based on WHO BMD T-score classification and TBS tertile were considered using Cox regression models to estimate covariate-adjusted (including sex) hazard ratios (aHR, 95%CI) for incident fracture by category, and each SD decrement in BMD and TBS. The study included 2799 individuals (77% female, mean age 32years). Mean (SD) minimum T-score was - 0.9 (1.1) and TBS 1.355 (0.114); 7% had osteoporosis and 13% were in the lowest TBS tertile. Incident major osteoporotic fracture (MOF) and any fracture risk was elevated in those with osteopenia (aHRs 1.20/1.45) and osteoporosis (aHRs 4.60/5.16). Fracture risk was unrelated to TBS tertile. Each SD decrement in BMD was associated with increased MOF risk (aHR 1.64) and any fracture (aHR 1.71); lower TBS was unrelated to fractures. In young adults, low BMD, but not low TBS, was predictive of MOF and any fracture. Routine clinical TBS measurement is not recommended for young adults. Further study is indicated to evaluate whether TBS is beneficial in subsets of younger adults.

Between and within calibration variation: implications for internal quality control rules

The variability between calibrations can be larger than the within calibration variation for some measurement procedures, that is a large CVbetween:CVwithin ratio. In this study, we examined the false rejection rate and probability of bias detection of quality control (QC) rules at varying calibration CVbetween:CVwithin ratios. Historical QC data for six representative routine clinical chemistry serum measurement procedures (calcium, creatinine, aspartate aminotransferase, thyrotrophin, prostate specific antigen and gentamicin) were extracted to derive the CVbetween:CVwithin ratios using analysis of variance. Additionally, the false rejection rate and probability of bias detection of three 'Westgard' QC rules (2:2S, 4:1S, 10X) at varying CVbetween:CVwithin ratios (0.1-10), magnitudes of bias, and QC events per calibration (5-80) were examined through simulation modelling. The CVbetween:CVwithin ratios for the six routine measurement procedures ranged from 1.1 to 34.5. With ratios >3, false rejection rates were generally above 10%. Similarly for QC rules involving a greater number of consecutive results, false rejection rates increased with increasing ratios, while all rules achieved maximum bias detection. Laboratories should avoid the 2:2S, 4:1S and 10X QC rules when calibration CVbetween:CVwithin ratios are elevated, particularly for those measurement procedures with a higher number of QC events per calibration.

Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study.

Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort). A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region. This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.

Metal mixture exposures and multiplexed autoantibody screening in Navajo communities exposed to uranium mine wastes

BackgroundEnvironmental exposures to metals in uranium mining wastes and drinking water were documented in more than half of the 1304 Navajo community members of the Diné Network for Environmental Health (DiNEH) Project, the first comprehensive assessment of exposures to these metals and community health on the Navajo Nation. ObjectiveEvaluate environmental exposures among participants who provided blood and urine samples using multiplexed autoantibody positivity as an early effect biomarker. MethodsSurvey and geospatial location data, well water quality, and metals biomonitoring were used to assess exposures to mixed-metal wastes from 100 abandoned uranium waste sites. ResultsWe observed that the prevalence of multiplexed autoantibody positivity in 239 participants was more than double that reported for the U.S. population (27.2% v. 13.8%) even though the national prevalence was generated using a different assay, the HEp-2 cell-based antinuclear antibody test. Increased risk of multiplexed autoantibody screening positivity (OR = 3.07,95%CI 1.15–8.22) was found among DiNEH study people who lived close to uranium mine and milling wastes and consumed metals in drinking water. Associations for females were even stronger when they lived closed to contaminated uranium mining and milling sites. Anti-U1-RNP antibodies were associated with water consumption of nickel. ConclusionProximity to waste sites and consumption of metals in water even below current drinking water standards were associated with perturbations of immune tolerance. These findings are consistent with previous studies of autoimmunity in the local population and demonstrate that multiplexed autoantibody screening method has a potential as sentinel indicator of exposures to environmental metals. Impact statementThis is the first, community-engaged environmental health study in exposed Navajo communities that applied clinical multiplexed testing in risk assessment of environmental metals associated with abandoned, unremediated uranium mining and milling waste sites. Routine clinical autoimmunity measures could be used as early effect biomarkers of environmental metal exposures.

Functional indices of vitamin D status and consequences of vitamin D deficiency

Serum 25-hydroxyvitamin D3 [25(OH)D3] concentrations are currently recognized as the functional status indicator for vitamin D. Evidence is reviewed that shows that serum 25(OH)D3 concentrations of &lt; 80 nmol/L are associated with reduced calcium absorption, osteoporosis, and increased fracture risk. For typical older individuals, supplemental oral intakes of ~1300 IU/d are required to reach the lower end of the optimal range. Evidence of substantial problems in routine clinical measurement of serum 25(OH)D3 concentrations among patients is cited. There is great need for standardization and improved reproducibility and sensitivity of measurements of serum 25(OH)D3 concentrations

Whole blood microRNAs capture systemic reprogramming and have diagnostic potential in patients with biliary tract cancer.

Late diagnosis is a critical factor undermining clinical management of patients with biliary tract cancer (BTC). While biliary tumours display extensive inter-patient heterogeneity, the host immune response may be comparatively homogenous, providing diagnostic opportunities. Herein, we investigated whether cancer-associated systemic reprogramming could be detected non-invasively to improve diagnosis of BTC. In this prospective Danish study, whole blood (WB) microRNA (miRNA) profiling was performed in samples from 218 patients with BTC, 99 healthy participants, and 69 patients with differential diagnoses split into discovery (small RNA-sequencing) and validation (RT-qPCR) cohorts. miRNA expression and activity were further investigated in 119 and 660 BTC tissues, respectively. Four WB miRNAs (let-7a-3p, miR-92b-5p, miR-145-3p, miR-582-3p) were identified and validated as diagnostic of BTC on univariable analysis. Two diagnostic miRNA indexes were subsequently identified that were elevated in patients with BTC and in patients with differential diagnoses, compared to healthy participants. The combination of these miRNA indexes with serum CA 19-9 significantly improved the diagnostic performance of CA 19-9 alone, consistently achieving superior AUC values irrespective of clinical setting (minimum AUC >0.84) or tumour location (minimum AUC >0.87). The diagnostic information captured by miRNA indexes was not recapitulated by routine clinical measurements. Index miRNA expression in BTC tissues was associated with distinct pathobiological and immune features. WB miRNA profiles are altered in patients with BTC. Quantification of miRNA indexes in combination with serum CA 19-9 has the potential to improve early diagnosis of BTC, pending further validation. Surgery is currently the only curative intervention for patients with biliary tract cancer (BTC). However, resection is not possible for most patients who are diagnosed with late-stage disease. With the aim of identifying new early diagnostic opportunities, we analysed circulating microRNAs (small non-coding RNAs whose role in cancer is being increasingly recognised) in whole blood samples. We identified a microRNA signature that could distinguish patients with BTC from healthy participants. These miRNAs significantly improved the diagnostic potential of the routinely measured biomarker, CA 19-9, and were implicated in distinct immune processes in tumour tissues.

Discordance In Fasting And Postprandial Indices Of Glycemic Dysregulation In Individuals With Spinal Cord Injury

Fasting levels of glucose and insulin are routine clinical measures used to diagnose type-2 diabetes. However, individuals with spinal cord injury (SCI) often present with clinically normal fasting glucose but have impaired postprandial responses to a meal challenge. PURPOSE: We aimed to characterize the postprandial glycemic responses and assess the prevalence of glycemic dysregulation using fasting and postprandial indices in individuals with SCI. METHODS: Sixteen men with chronic SCI reported to the laboratory after an overnight fast to undergo either a 2-hour: oral glucose tolerance test (OGTT) using a 75-g (~300 kcal) glucose load (n = 8) or; a mixed meal tolerance test (MMTT, (1037 ± 148 kcal: 45% CHO, 37% fat, 18% PRO) (n = 8). Serial measurements of systemic glucose and insulin concentrations at baseline and in response to the OGTT/MMTT were converted into summary statistics: Insulin Resistance was estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR); whole body Insulin Sensitivity Index was estimated using methods described by Matsuda (ISIMatsuda). RESULTS: There were no differences between groups in age (p = 1.0), body mass index (p = 0.87), cardiorespiratory fitness (p = 0.26), fasting glucose (p = 0.53) or insulin (p = 0.19). In the MMTT group, 3 (38%) individuals were identified as prediabetic (fasting plasma glucose (FPG), 7.3 ± 0.9 mmol/L) and 0 individuals had impaired insulin resistance (HOMA2-IR, 1.05 ± 0.6). However, 5 (63%) individuals had impaired postprandial insulin sensitivity (ISIMatsuida, 2.2 ± 0.4). In the OGTT group, 2 (25%) individuals were prediabetic (FPG, 6.2 ± 0.2 mmol/L), 2 (25%) different individuals had impaired insulin resistance (HOMA2-IR, 3.2 ± 0.9), but 7 (88%) individuals had impaired postprandial insulin sensitivity (ISIMatsuida, 2.3 ± 0.9). CONCLUSIONS: In this small study, an OGTT identified more SCI participants with glucose dysregulation than MMTT. Postprandial measures of insulin sensitivity identified a greater proportion of SCI participants with impaired glycemic control and may have preferred utility in identifying individuals at high risk of diabetes. Future studies should compare and contrast the specificity and sensitivity of fasting and postprandial methods in this high-risk population.

Prognosis of systemic inflammation at an early stage of cirrhosis using the monocyte-to-lymphocyte ratio during malnutrition risk screening: a prospective cohort study

ABSTRACT Objective To determine whether the monocyte-to-lymphocyte ratio (MLR), as a systemic inflammation index, predicts malnutrition risk during the early stages of cirrhosis. Methods We conducted a single-center prospective cohort study, enrolling patients from June 2016 to September 2020. The patients underwent malnutrition risk assessments upon admission. The patients were classified into five clinical stages according to portal hypertension. The malnutrition risk was scored using the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) and validated by the Nutritional Risk Screening 2002 (NRS-2002) or Liver Disease Undernutrition Screening Tool (LDUST). Routine clinical laboratory measurements were performed to calculate the MLR, Child–Turcotte–Pugh (CTP) class, and model for end-stage liver disease (MELD) score. The patients were followed up for 2 years. Results Among the 154 patients with cirrhosis, 60 had compensated cirrhosis and 94 had decompensated cirrhosis. The optimal cutoff value of the MLR, >0.4, was effective in predicting malnutrition related to death or liver transplantation. Those with a high malnutrition risk defined by the NRS-2002 or RFH-NPT had a higher MLR than those with a low malnutrition risk. For patients with class A CTP cirrhosis or a MELD score of <10, an MLR cutoff of <0.4 significantly distinguished more patients with a low malnutrition risk than those with a high malnutrition risk. Both the RFH-NPT score and MLR increased significantly across the decompensated cirrhosis substages. Interestingly, the MLR exhibited a positive correlation with the RFH-NPT score until varices appeared, but the correlation was the highest at the substage of a history of variceal bleeding (r = 0.714, P = 0.009). Multivariable analysis demonstrated that an MLR of >0.4 was an independent factor for malnutrition risk by screening with the RFH-NPT, and this was confirmed using the LDUST and NRS-2002. Conclusion Immune-related inflammatory dysfunction predicts malnutrition risk during the early stages of cirrhosis.

Evaluating future risk of NAFLD in adolescents: a prediction and decision curve analysis

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the commonest liver condition in the western world and is directly linked to obesity and the metabolic syndrome. Elevated body mass index is regarded as a major risk factor of NAFL (steatosis) and NAFLD fibrosis. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we sought to investigate whether other variables from adolescence could improve prediction of future NAFL and NAFLD fibrosis risk at 24 years, above BMI and sex.MethodsAged 24 years, 4018 ALSPAC participants had transient elastography (TE) and controlled attenuation parameter (CAP) measurement using Echosens 502 Touch. 513 participants with harmful alcohol consumption were excluded. Logistic regression models examined which variables measured at 17 years were predictive of NAFL and NAFLD fibrosis in young adults. Predictors included sex, BMI, central adiposity, lipid profile, blood pressure, liver function tests, homeostatic model assessment for insulin resistance (HOMA-IR), and ultrasound defined NAFL at 17 years (when examining fibrosis outcomes). A model including all these variables was termed “routine clinical measures”. Models were compared using area under the receiver operator curve (AUROC) and Bayesian Information Criterion (BIC), analysis, which penalises model complexity. Models were tested in all participants and those with overweight or obese standardised BMIs (BMI SDS) centiles at the 17-year time point. A decision curve analysis (DCA) was performed to evaluate the clinical utility of models in overweight and obese adolescents predicting NAFLD fibrosis at a threshold probability of 0.1.ResultsThe “routine clinical measures” model had the highest AUROC for predicting NAFL in all adolescent participants (AUROC 0.79 [SD 0.00]) and those with an overweight/obese BMI SDS centile (AUROC 0.77 [SD 0.01]). According to BIC analysis, insulin resistance was the best predictor of NAFL in all adolescents, whilst central adiposity was the best predictor in those with an overweight/obese BMI SDS centile. The “routine clinical measures” model also had the highest AUROC for predicting NAFLD fibrosis in all adolescent participants (AUROC 0.78 [SD 0.02]) and participants with an overweight/obese BMI SDS centile (AUROC 0.84 [SD 0.03]). However, following BIC analysis, BMI was the best predictor of NAFLD fibrosis in all adolescents including those with an overweight/obese BMI SDS centile. A decision curve analysis examining overweight/obese adolescent participants showed the model that had the greatest net benefit for increased NAFLD fibrosis detection, above a treat all overweight and obese adolescents’ assumption, was the “routine clinical measures” model. However, the net benefit was marginal (0.0054 [0.0034–0.0075]).ConclusionIn adolescents, routine clinical measures were not superior to central adiposity and BMI at predicting NAFL and NAFLD fibrosis respectively in young adulthood. Additional routine clinical measurements do provide incremental benefit in detecting true positive fibrosis cases, but the benefit is small. Thus, to reduce morbidity and mortality associated with NASH cirrhosis in adults, the ultimate end point of NAFLD, the focus must be on obesity management at a population level.

Postprandial and Fasting Metabolic Signatures: Insights From the ZOE PREDICT 1 Study

ObjectivesPostprandial metabolomic signatures, although not well characterized, may provide greater insight into individuals’ responses to food and subsequent cardiometabolic disease risk compared to fasting and routine clinical measures. Using the PREDICT 1 cohort, we assessed postprandial changes and inter-individual variability in metabolites sequenced by NMR. MethodsThe ZOE PREDICT 1 study (n = 1,002 healthy UK adults; NCT03479866) measured 250 metabolite parameters (Nightingale Health NMR panel, related to lipids, amino acids, glycolysis, ketones, and glycoprotein acetyls (GlycA)) by venous cannulation at fasting and postprandially after a mixed nutrient sequential test meal (4 and 6 h after meal 1, 3.7 MJ; meal 2 given at 4 h, 2.2 MJ). Postprandial changes in metabolites and their inter-individual variability (median absolute difference from the median (MADM)/median (%)) were evaluated. Associations (Spearman’s correlations) and differences in variances (Fligner-Killeen test) were assessed between fasting and postprandial (6 h) measures. ResultsA significant 6 h postprandial change from fasting was seen in 85% of metabolites; of which, 47% increased, and 53% decreased (Kruskal-Wallis p < 0.05 for all). Ketone bodies and very-large lipoprotein particles showed the greatest changes. Fasting and postprandial measures had large, yet similar, inter-individual variability (MADM/median; 15% at 0, 4 and 6 h (mean for all)) and were strongly correlated (r > 0.8; 71% of measures), although ketone bodies, glucose, branched chain amino acids and LDL diameter were only weakly correlated (r < 0.5). Inter-individual patterns of response differed postprandially compared to fasting (Fligner-Killeen test of variance, p < 0.05). ConclusionsIn this large and generally healthy cohort, we demonstrate significant changes in circulating metabolites between the fasting and postprandial phase, as expected, within lipoprotein size and composition remodelling, glycolysis, essential amino acid and ketone body pathways. The large inter-individual variability in postprandial metabolite levels, suggests dietary challenges offer an opportunity for stratifying metabolic responses. Funding SourcesZOE Ltd.