Diabetes and Dyslipidemia Screening in Pediatric Practice.

The incidence of diabetes and hyperlipidemia are increasing at rapid rates in children. These conditions are associated with increased risk of macrovascular and microvascular complications causing major morbidity and mortality later in life. Early diagnosis and treatment can reduce the lifelong risk of complications from these diseases, exemplifying the importance of screening in the pediatric population. The following article presents a summary of the current guidelines for diabetes and hyperlipidemia screening in pediatric patients.

High-fat diet prevents the development of autoimmune diabetes in NOD mice.

AIMS: Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate the beta-cell autoimmune destruction. The rate of childhood obesity has risen in parallel to the proportion of T1D, suggesting high-fat diet (HFD)/obesity as potential environmental triggers for autoimmune diabetes. To explore this, non-obese diabetic (NOD) mice were subjected to HFD and monitored for the development of diabetes, insulitis and beta-cell stress. MATERIALS AND METHODS: Four-week-old female NOD mice were placed on HFD (HFD-NOD) or standard chow-diet. Blood glucose was monitored weekly up to 40 weeks of age, and glucose- and insulin-tolerance tests performed at 4, 10 and 15 weeks. Pancreata and islets were analysed for insulin secretion, beta-cell mass, inflammation, insulitis and endoplasmic reticulum stress markers. Immune cell levels were measured in islets and spleens. Stool microbiome was analysed at age 4, 8 and 25 weeks. RESULTS: At early ages, HFD-NOD mice showed a significant increase in body weight, glucose intolerance and insulin resistance; but paradoxically, they were protected from developing diabetes. This was accompanied by increased insulin secretion and beta-cell mass, decreased insulitis, increased splenic T-regulatory cells and altered stool microbiome. CONCLUSIONS: This study shows that HFD protects NOD mice from autoimmune diabetes and preserves beta-cell mass and function through alterations in gut microbiome, increased T-regulatory cells and decreased insulitis. Further studies into the exact mechanism of HFD-mediated prevention of diabetes in NOD mice could potentially lead to interventions to prevent or delay T1D development in humans.

Hypercalcemia in Patients with Williams-Beuren Syndrome.

OBJECTIVE: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.

Sarcopenia in COPD: prevalence, clinical correlates and response to pulmonary rehabilitation.

BACKGROUND: Age-related loss of muscle, sarcopenia, is recognised as a clinical syndrome with multiple contributing factors. International European Working Group on Sarcopenia in Older People (EWGSOP) criteria require generalised loss of muscle mass and reduced function to diagnose sarcopenia. Both are common in COPD but are usually studied in isolation and in the lower limbs. OBJECTIVES: To determine the prevalence of sarcopenia in COPD, its impact on function and health status, its relationship with quadriceps strength and its response to pulmonary rehabilitation (PR). METHODS: EWGSOP criteria were applied to 622 outpatients with stable COPD. Body composition, exercise capacity, functional performance, physical activity and health status were assessed. Using a case-control design, response to PR was determined in 43 patients with sarcopenia and a propensity score-matched non-sarcopenic group. RESULTS: Prevalence of sarcopenia was 14.5% (95% CI 11.8% to 17.4%), which increased with age and Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stage, but did not differ by gender or the presence of quadriceps weakness (14.9 vs 13.8%, p=0.40). Patients with sarcopenia had reduced exercise capacity, functional performance, physical activity and health status compared with patients without sarcopenia (p<0.001), but responded similarly following PR; 12/43 patients were no longer classified as sarcopenic following PR. CONCLUSIONS: Sarcopenia affects 15% of patients with stable COPD and impairs function and health status. Sarcopenia does not impact on response to PR, which can lead to a reversal of the syndrome in select patients.

Does pulmonary rehabilitation reduce peripheral blood pressure in patients with chronic obstructive pulmonary disease?

Pulmonary rehabilitation (PR) can improve aerobic exercise capacity, health-related quality of life and dyspnoea in patients with chronic obstructive pulmonary disease (COPD). Recent studies have suggested that exercise training may improve blood pressure and arterial stiffness, albeit in small highly selected cohorts. The aim of the study was to establish whether supervised outpatient or unsupervised home PR can reduce peripheral blood pressure. Resting blood pressure was measured in 418 patients with COPD before and after outpatient PR, supervised by a hospital-based team (HOSP). Seventy-four patients with COPD undergoing an unsupervised home-based programme acted as a comparator group (HOME). Despite significant improvements in mean (95% confidence interval) exercise capacity in the HOSP group (56 (50-60) m, p < 0.001) and HOME group (30 (17-42) m, p < 0.001) systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) did not change in either the HOSP (SBP: p = 0.47; DBP: p = 0.06; MAP: p = 0.38) or HOME group (SBP: p = 0.67; DBP: p = 0.38; MAP: p = 0.76). Planned subgroup analysis of HOSP patients with known hypertension and/or cardiovascular disease showed no impact of PR upon blood pressure. PR is unlikely to reduce blood pressure, and by implication, makes a mechanism of action in which arterial stiffness is reduced, less likely.

Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: referrals, uptake and adherence.

RATIONALE: Several randomised controlled trials support the provision of early pulmonary rehabilitation (PR) following hospitalisation for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there is little real-world data regarding uptake, adherence and completion rates. METHODS: An audit was conducted to prospectively document referral, uptake, adherence and completion rates for early post-hospitalisation outpatient PR in Northwest London over a 12-month period. RESULTS: Out of 448 hospital discharges for AECOPD, 90 referrals for post-hospitalisation PR were received. Only 43 patients received and completed PR (9.6% of all hospital discharges) despite a fully commissioned PR service. CONCLUSIONS: Despite the strong evidence base, there are poor referral and uptake rates for early outpatient PR following hospitalisation for AECOPD, with only a small proportion of the intended target population receiving this intervention.

The Clinical COPD Questionnaire: response to pulmonary rehabilitation and minimal clinically important difference.

BACKGROUND: The Clinical COPD Questionnaire (CCQ) is a simple 10-item, health-related quality of life questionnaire (HRQoL) with good psychometric properties. However, little data exists regarding the responsiveness of the CCQ to pulmonary rehabilitation (PR) or the minimal clinically important difference (MCID). The study aims were to assess the responsiveness of the CCQ to PR, to compare the responsiveness of the CCQ to other HRQoL questionnaires and to provide estimates for the MCID. METHODS: The CCQ, St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ) and COPD Assessment Test (CAT) were measured in 261 patients with COPD before and after outpatient PR. Pre to post PR changes and Cohen's effect size were calculated. Changes in CCQ were compared with changes in other HRQoL questionnaires. Using an anchor-based approach and receiver operating characteristic (ROC) curves, the CCQ change cutoffs that identified patients achieving the known MCID for other health status questionnaires with PR were identified. RESULTS: The CCQ, SGRQ, CRQ and CAT all significantly improved with PR with an effect size of -0.39, -0.33, 0.62 and -0.25, respectively. CCQ change correlated significantly with change in SGRQ, CRQ and CAT (r=0.48, -0.56, 0.54, respectively; all p<0.001). ROC curves consistently identified a CCQ change cutoff of -0.4 as the best discriminating value to identify the MCID for the SGRQ, CRQ and CAT (area under curve: 0.71, 0.75 and 0.77, respectively; all p<0.001). CONCLUSIONS: The CCQ is responsive to PR with an estimated clinically important improvement of -0.4 points. The CCQ is a practical alternative to more time-consuming measures of HRQoL.

The 4-metre gait speed in COPD: responsiveness and minimal clinically important difference.

Usual gait speed is a consistent predictor of adverse outcomes in community-dwelling elderly people. The reliability and validity of the 4-m gait speed (4MGS) has recently been demonstrated in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the responsiveness of the 4MGS and to estimate the minimal clinically important difference (MCID). In 301 COPD patients, 4MGS and incremental shuttle walk (ISW) were measured before and after pulmonary rehabilitation. 4MGS and ISW were also measured at baseline and 1 year later in a separate cohort of 162 COPD patients. The MCID of 4MGS was estimated using distribution and anchor-based methods. 4MGS improved significantly with pulmonary rehabilitation (mean change 0.08 m·s(-1), p<0.001). The minimal detectable change at 95% confidence was 0.11 m·s(-1). The MCID was estimated at 0.11 m·s(-1) (anchored against ISW) and 0.08 m·s(-1) (anchored against self-reported improvement). The effect size for 4MGS was greatest in frail individuals. After 12 months, mean 4MGS declined by 0.04 m·s(-1). When anchored against a decline of more than the MCID for ISW, change in 4MGS was -0.11 m·s(-1). The 4MGS is responsive to pulmonary rehabilitation and longitudinal change in COPD, and has potential as a simple functional assessment tool in COPD. The 4MGS may be particularly useful in frail individuals with COPD.

Clinical COPD Questionnaire in patients with chronic respiratory disease.

BACKGROUND AND OBJECTIVE: The Clinical Chronic Obstructive Pulmonary Disease (COPD) Questionnaire (CCQ) is an easy to complete, health-related quality of life questionnaire which has been well-validated in COPD. The responsiveness of the CCQ in chronic respiratory disease patients other than COPD has not been previously described. The study aims were to determine if the CCQ in chronic respiratory disease correlates with other health related quality of life questionnaires, to assess the responsiveness of the CCQ to pulmonary rehabilitation and to determine the minimum important difference. METHODS: The CCQ, COPD Assessment Test (CAT), the Chronic Respiratory Questionnaire (CRQ) and St George's Respiratory Questionnaire (SGRQ) were measured in 138 chronic respiratory disease patients completing pulmonary rehabilitation. Change in CCQ with pulmonary rehabilitation was correlated with change in the other questionnaires. The minimum important difference of the CCQ was calculated using distribution and anchor-based approaches. RESULTS: The CCQ, CAT, CRQ and SGRQ improved significantly with rehabilitation with effect sizes of -0.43, -0.26, 0.62, -0.37. Change in CCQ correlated significantly with CAT, CRQ and SGRQ (r = 0.53, -0.64, 0.30, all P < 0.0001). The minimum important difference was -0.42 at the population level and -0.4 at the individual level. CONCLUSIONS: The CCQ is responsive to pulmonary rehabilitation in chronic respiratory disease patients, with an MID estimated at -0.4 at the individual level.

The five-repetition sit-to-stand test as a functional outcome measure in COPD.

BACKGROUND: Moving from sitting to standing is a common activity of daily living. The five-repetition sit-to-stand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking. AIMS: To determine the reliability, validity and responsiveness of the 5STS in patients with COPD. METHODS: Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods. RESULTS: Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=-0.59, -0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s. CONCLUSIONS: The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings.

Reliability and validity of 4-metre gait speed in COPD.

In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George's Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to "slow" (<0.8 m·s(-1)) or "normal" 4MGS (≥0.8 m·s(-1)). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (ρ = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (ρ = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD.

Response of the COPD Assessment Test to pulmonary rehabilitation in unselected chronic respiratory disease.

BACKGROUND AND OBJECTIVE: The COPD Assessment Test (CAT) is a recently introduced, simple-to-use health status instrument that takes less time to complete than better-established health status instruments. In chronic obstructive pulmonary disease (COPD) patients, the CAT improves with pulmonary rehabilitation (PR), and changes correlate with improvements in longer-established health status instruments such as the Chronic Respiratory Questionnaire (CRQ). Increasing numbers of non-COPD patients are referred for PR, but it is not known whether the CAT is responsive to PR in these populations. METHODS: The CAT score was prospectively measured in 365 consecutive patients (255 COPD, 110 non-COPD) before and after an 8-week PR programme. Pre to post change in CAT was calculated for COPD and non-COPD patients, and correlated with change in the CRQ. RESULTS: For both non-COPD and COPD patients, there was a similar and significant improvement in the mean (95% confidence interval) CAT score following PR (non-COPD: -2.1 (-1.0, -3.2) vs COPD: -3.0 (-2.2, -3.8); P = 0.19). Change in CAT was significantly correlated with all domains of the CRQ in non-COPD patients (all P < 0.01). CONCLUSIONS: As in COPD patients, the CAT is immediately responsive to PR in non-COPD patients. Even in unselected chronic respiratory disease patients undergoing PR, the CAT is a practical alternative to longer-established health status questionnaires.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Stanford Seven-Day Physical Activity Recall questionnaire in COPD.

Quantification of daily physical activity is of clinical interest in chronic obstructive pulmonary disease (COPD). Objective measures using activity monitors may take several days to obtain reliable results. The aim of our study was to evaluate the Stanford Seven-Day Physical Activity Recall questionnaire (PAR) against the SenseWear armband (SWA) and compare its validity with three other physical activity questionnaires. 43 COPD patients wore the SWA for 7 days. Patients completed the PAR, Baecke, Physical Activity Scale for the Elderly (PASE) and Zutphen questionnaires. Spearman rank correlation, intraclass correlation coefficients (ICC) and receiver-operating characteristics (ROC) curves were used to assess the relationship between the questionnaires and SWA. Assessed by PAR, time spent at ≥3.0 metabolic equivalents (METs) correlated significantly (r=0.54, p<0.001) with equivalent measures from SWA, with an ICC of 0.40. No relationship was seen between the other questionnaires and the SWA. The PAR predicted active patients (≥30 min at ≥3.0 METs or a physical activity level (PAL) ≥1.55) and very inactive patients (PAL <1.40) with an area under ROC curve of 0.83, 0.77 and 0.70, respectively. While the PAR did not measure physical activity sufficiently accurately to make individual recommendations, it was able to identify COPD patients at extremes of the physical activity spectrum, potentially reducing the number of patients requiring direct measurement.

The COPD Assessment Test (CAT): short- and medium-term response to pulmonary rehabilitation.

BACKGROUND: The COPD Assessment Test (CAT) is a recently introduced instrument to assess health-related quality of life in COPD. We aimed to evaluate the longitudinal change in CAT following Pulmonary Rehabilitation (PR), and test the relationship between CAT and CRQ-Self Report (SR) over time. We hypothesised that the CAT would show similar responsiveness to PR as the CRQ-SR both in the short and medium-term. METHODS: 118 COPD patients completed an eight-week outpatient multidisciplinary PR programme. CAT, CRQ-SR and the incremental shuttle walk (ISW) were measured prior to starting PR (T1), completion of PR (T2) and 6 months after completion of PR (T3). RESULTS: There was a significant improvement in CAT, CRQ-SR and ISW immediately following PR (p < 0.001). Although there was decline between T2 and T3, CAT, CRQ-SR and ISW remained significantly better at T3 compared with T1 (ANOVA p < 0.001). Both between T1-T2 and between T2-T3, change in CAT correlated significantly with change in CRQ (both r = -0.44 and p < 0.001). The slope of the relationship between CAT change and CRQ-SR change at T1-T2 and T2-T3 was not significantly different (ANCOVA: intercept p = 0.79, interaction effect p = 0.95). CONCLUSIONS: In COPD, the CAT score is immediately responsive to PR and remains improved at 6 months. There is no significant difference in the short and medium term changes in the CAT and CRQ-SR following PR. We propose that for most clinical indications for assessing health-related quality of life in COPD, the CAT is a robust and practical alternative to longer-established instruments such as the CRQ-SR.

Genetic Reduction of Glucose Metabolism Preserves Functional ß-Cell Mass in KATP-Induced Neonatal Diabetes.

ß-Cell failure and loss of ß-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in ß-cell exhaustion/failure, loss of ß-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased ß-cell metabolism is responsible for ß-cell failure and that reducing glucose metabolism will prevent loss of ß-cell mass. To test this, KATP-GOF mice were crossed with mice carrying ß-cell-specific glucokinase haploinsufficiency (GCK+/-), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/- mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/- mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/- mice. Strikingly, KATP-GOF/GCK+/- mice demonstrated preserved ß-cell mass and identity compared with the marked decrease in ß-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/- mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing ß-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and ß-cell failure independently of compensatory insulin hypersecretion and ß-cell exhaustion.

SARS-CoV-2 infection of islet ß cells: Evidence and implications.

The health of insulin-producing ß cells is critical for normoglycemia. Wu et al.1 and Tang et al.2 provide evidence in vitro that ß cells can be infected by SARS-CoV-2 virus, possibly contributing to worsening hyperglycemia seen during the COVID-19 pandemic.