Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD).
The ...multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations.
The panel found varying quality and availability of evidence and made the following judgments:
) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia,
) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia,
) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia,
) a conditional recommendation for ambulatory liquid-oxygen use in patients who are mobile outside the home and require >3 L/min of continuous-flow oxygen during exertion (very-low-quality evidence), and
) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (best-practice statement).
These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.
Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25OHD) and calcium supplementation increase birth weight. However, limitations of many trials were ...highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.
We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25OHD and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g 95% CI -2.48 to 2.42 g, p = 0.981 per 10% higher maternal 25OHD). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g 95% CI 2.15-9.73, p = 0.002 per 10% higher maternal 25OHD), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g 95% CI -44 to 5 g, p = 0.116 per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g 95% CI 121-236 g, p = 1.43 × 10-9 per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.
Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Babies of women with heterozygous pathogenic glucokinase (GCK) variants causing mild fasting hyperglycemia are at risk of macrosomia if they do not inherit the variant. ...Conversely, babies who inherit a pathogenic hepatocyte nuclear factor 4α (HNF4A) diabetes variant are at increased risk of high birth weight. Noninvasive fetal genotyping for maternal pathogenic variants would inform pregnancy management.
Methods
Droplet digital PCR was used to quantify reference and variant alleles in cell-free DNA extracted from blood from 38 pregnant women heterozygous for a GCK or HNF4A variant and to determine fetal fraction by measurement of informative maternal and paternal variants. Droplet numbers positive for the reference/alternate allele together with the fetal fraction were used in a Bayesian analysis to derive probability for the fetal genotype. The babies’ genotypes were ascertained postnatally by Sanger sequencing.
Results
Droplet digital PCR assays for GCK or HNF4A variants were validated for testing in all 38 pregnancies. Fetal fraction of ≥2% was demonstrated in at least 1 cell-free DNA sample from 33 pregnancies. A threshold of ≥0.95 for calling homozygous reference genotypes and ≤0.05 for heterozygous fetal genotypes allowed correct genotype calls for all 33 pregnancies with no false-positive results. In 30 of 33 pregnancies, a result was obtained from a single blood sample.
Conclusions
This assay can be used to identify pregnancies at risk of macrosomia due to maternal monogenic diabetes variants.
Aims/hypothesis
Classically, type 1 diabetes is thought to proceed to absolute insulin deficiency. Recently developed ultrasensitive assays capable of detecting C-peptide under 5 pmol/l now allow ...very low levels of C-peptide to be detected in patients with long-standing type 1 diabetes. It is not known whether this low-level endogenous insulin secretion responds to physiological stimuli. We aimed to assess how commonly low-level detectable C-peptide occurs in long-duration type 1 diabetes and whether it responds to a meal stimulus.
Methods
We performed a mixed-meal tolerance test in 74 volunteers with long-duration (>5 years) type 1 diabetes, i.e. with age at diagnosis 16 (9–23) years (median interquartile range) and diabetes duration of 30 (19–41) years. We assessed fasting and stimulated serum C-peptide levels using an electrochemiluminescence assay (detection limit 3.3 pmol/l), and also the urinary C-peptide:creatinine ratio (UCPCR).
Results
Post-stimulation serum C-peptide was detectable at very low levels (>3.3 pmol/l) in 54 of 74 (73%) patients. In all patients with detectable serum C-peptide, C-peptide either increased (
n
= 43, 80%) or stayed the same (
n
= 11) in response to a meal, with no indication of levels falling (
p
< 0.0001). With increasing disease duration, absolute C-peptide levels fell although the numbers with detectable C-peptide remained high (68%, i.e. 25 of 37 patients with >30 years duration). Similar results were obtained for UCPCR.
Conclusions/interpretation
Most patients with long-duration type 1 diabetes continue to secrete very low levels of endogenous insulin, which increase after meals. This is consistent with the presence of a small number of still functional beta cells and implies that beta cells are either escaping immune attack or undergoing regeneration.
ObjectiveSubclinical hypothyroidism and isolated hypothyroxinaemia in pregnancy have been associated with an increased risk of gestational diabetes. We aimed to ascertain if these women have a worse ...metabolic phenotype than euthyroid pregnant women.Design, subjects and methodsWe recruited 956 healthy Caucasian women with singleton, non-diabetic pregnancies from routine antenatal clinics. Detailed anthropometric measurements (including BMI and skinfold thickness) and fasting blood samples (for TSH, free thyroxine (FT4), free triiodothyronine (FT3), HbA1c, lipid profile, plasma glucose and insulin resistance (HOMA-IR) analysis) were obtained at 28 weeks gestation.ResultsIn comparison to euthyroid women (n=741), women with isolated hypothyroxinaemia (n=82) had significantly increased BMI (29.5 vs 27.5 kg/m2, P<0.001), sum of skinfolds (57.5 vs 51.3 mm, P=0.002), fasting plasma glucose (4.5 vs 4.3 mmol/l, P=0.01), triglycerides (2.3 vs 2.0 mmol/l, P<0.001) and HOMA-IR (2.0 vs 1.3, P=0.001). Metabolic parameters in women with subclinical hypothyroidism (n=133) were similar to those in euthyroid women. Maternal FT4 was negatively associated with BMI (r=−0.22), HbA1c (r=−0.14), triglycerides (r=−0.17), HOMA-IR (r=−0.15) but not total/HDL cholesterol ratio (r=−0.03). Maternal FT3:FT4 ratio was positively associated with BMI (r=0.4), HbA1c (r=0.21), triglycerides (r=0.2), HOMA–IR (r=0.33) and total/HDL cholesterol ratio (r=0.07). TSH was not associated with the metabolic parameters assessed.ConclusionsIsolated hypothyroxinaemia, but not subclinical hypothyroidism, is associated with adverse metabolic phenotype in pregnancy, as is decreasing maternal FT4 and increasing FT3:FT4 ratio. These associations may be a reflection of changes in the thyroid hormone levels secondary to increase in BMI rather than changes in thyroid hormone levels affecting body weight and related metabolic parameters.
To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in ...patients with type 2 diabetes.
We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with β-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change.
Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ≤ 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol -0.5 vs. -1.4%, P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol -0.2 vs. -1.4%, P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change.
Clinical markers of low β-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes.
Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of ...complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neonatal diabetes presents <6 months of life but delays in recognition result in presentation with life-threatening hyperglycaemia/diabetic ketoacidosis. Early identification and rapid genetic ...diagnosis is crucial and ensures correct treatment/management. Adding ‘glucose’ to newborn bloodspot screening (NBS) could aid prompt detection but requires evidence of parental acceptance.ObjectivesIncrease understanding of parental experience of presentation/recognition of neonatal diabetes and perceptions of glucose testing within NBS.SettingUK families confirmed with a genetic diagnosis of neonatal diabetes, November 2014–2018, were invited to participate.ParticipantsIn-depth qualitative interviews were conducted with 10 parents of 14 children. 8 had transient neonatal diabetes: KCNJ11 (n=5), ABCC8 (n=1), 6q24 (n=2), 6 had permanent neonatal diabetes: KCNJ11 (n=4), INS (n=1), homozygous GCK (n=1).Primary and secondary outcome measuresInterviews audio recorded, transcribed and subjected to thematic content analysis.Results3 key themes emerged:Babies were extremely ill at hospital admission, with extended stays in intensive care required.Identification of diabetes was not ‘standardised’ and perceived a ‘chance’ finding.Adding glucose to NBS was universally considered extremely positive.ConclusionsDiagnosis of neonatal diabetes is frequently delayed, resulting in critically ill presentation with prolonged intensive care support, additional healthcare costs and familial distress. Potential to detect hyperglycaemia earlier was universally endorsed by parents with no negative consequences identified. Although further study including a larger number of individuals is needed to confirm our findings this study provides the first evidence of acceptability of glucose testing fulfilling Wilson-Jungner criteria for implementation within the NBS programme.
Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low ...birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight.
In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496.
We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone TSH with normal free thyroxine FT
) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT
with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio OR 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (p
=0·10). Each 1 SD increase in FT
concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second.
Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT
(even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy.
Netherlands Organization for Scientific Research (grant 401.16.020).
A precision approach to type 2 diabetes therapy would aim to target treatment according to patient characteristics. We examined if measures of insulin resistance and secretion were associated with ...glycemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy.
We evaluated whether markers of insulin resistance and insulin secretion were associated with 6-month glycemic response in a prospective study of noninsulin-treated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents PRIBA study;
= 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink CPRD;
= 23,001). In CPRD, we evaluated associations between baseline markers and 3-year durability of response. To test the specificity of findings, we repeated analyses for glucagon-like peptide 1 (GLP-1) receptor agonists (PRIBA,
= 339; CPRD,
= 4,464).
In PRIBA, markers of higher insulin resistance (higher fasting C-peptide
= 0.03, HOMA2 insulin resistance
= 0.01, and triglycerides
< 0.01) were associated with reduced 6-month HbA
response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA
response (both
< 0.01). A subgroup defined by obesity (BMI ≥30 kg/m
) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA
reduction 5.3 95% CI 1.8, 8.6 mmol/mol 0.5% obese and high triglycerides vs. 11.3 8.4, 14.1 mmol/mol 1.0% nonobese and normal triglycerides;
= 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 1.16, 1.41;
< 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists.
Markers of higher insulin resistance are consistently associated with reduced glycemic response to DPP-4 inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP-4 inhibitor therapy.
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