The importance of nonobstructive plaque characteristics in symptomatic and asymptomatic coronary artery disease.

BACKGROUND: We examined obstructive and nonobstructive plaque volumes in populations with subclinical and clinically manifested coronary artery disease (CAD) using quantitative computed tomography (QCT). METHODS: 855 participants with CAD (274 asymptomatic individuals, 254 acute chest pain patients without acute coronary syndrome (ACS), and 327 patients with ACS) underwent QCT of proximal coronary segments to assess participant-level plaque volumes of dense calcium, fibrous, fibrofatty, and necrotic core tissue. RESULTS: Nonobstructive (<50% stenosis) plaque volumes were greater than obstructive plaque volumes, irrespective of population (all p<0.0001): Asymptomatic individuals (mean (95% CI)): 218 [190-250] vs. 16 [12-22] mm3; acute chest pain patients without ACS: 300 [263-341] vs. 51 [41-62] mm3; patients with ACS: 370 [332-412] vs. 159 [139-182] mm3. After multivariable adjustment, nonobstructive fibrous and fibrofatty tissue volumes were greater in acute chest pain patients without ACS compared to asymptomatic individuals (fibrous tissue: 122 [107-139] vs. 175 [155-197] mm3, p<0.01; fibrofatty tissue: 44 [38-50] vs. 71 [63-80] mm3, p<0.01. Necrotic core tissue was greater in ACS patients (29 [26-33] mm3) compared to both asymptomatic individuals (15 [13-18] mm3, p<0.0001) and acute chest pain patients without ACS (21 [18-24] mm3, p<0.05). Nonobstructive dense calcium volumes did not differ between the three populations: 29 [24-36], 29 [23-35], and 41 [34-48] mm3, p>0.3 respectively. CONCLUSION: Nonobstructive CAD was the predominant contributor to total atherosclerotic plaque volume in both subclinical and clinically manifested CAD. Nonobstructive fibrous, fibrofatty and necrotic core tissue volumes increased with worsening clinical presentation, while nonobstructive dense calcium tissue volumes did not.

Effects of prenatal exercise on gestational weight gain, obstetric and neonatal outcomes: FitMum randomized controlled trial.

BACKGROUND: To investigate the effects of two different exercise interventions during pregnancy on gestational weight gain (GWG) and obstetric and neonatal outcomes compared to standard care. Additionally, we aimed to improve standardization of GWG measurements by developing a model to estimate GWG for a standardized pregnancy period of 40 weeks and 0 days accounting for individual differences in gestational age (GA) at delivery. METHODS: In a randomized controlled trial we compared the effects of structured supervised exercise training (EXE) three times per week throughout pregnancy versus motivational counselling on physical activity (MOT) seven times during pregnancy with standard care (CON) on GWG and obstetric and neonatal outcomes. Uniquely, to estimate GWG for a standardized pregnancy period, we developed a novel model to predict GWG based on longitudinally observed body weights during pregnancy and at admission for delivery. Observed weights were fitted to a mixed effects model that was used to predict maternal body weight and estimate GWG at different gestational ages. Obstetric and neonatal outcomes, among them gestational diabetes mellitus (GDM) and birth weight, were obtained after delivery. GWG and the investigated obstetric and neonatal outcomes are secondary outcomes of the randomized controlled trial, which might be underpowered to detect intervention effects on these outcomes. RESULTS: From 2018-2020, 219 healthy, inactive pregnant women with median pre-pregnancy BMI of 24.1 (21.8-28.7) kg/m2 were included at median GA 12.9 (9.4-13.9) weeks and randomized to EXE (n = 87), MOT (n = 87) or CON (n = 45). In total 178 (81%) completed the study. GWG at GA 40 weeks and 0 days did not differ between groups (CON: 14.9 kg [95% CI, 13.6;16.1]; EXE: 15.7 kg [14.7;16.7]; MOT: 15.0 kg [13.6;16.4], p = 0.538), neither did obstetric nor neonatal outcomes. For example, there were no differences between groups in the proportions of participants developing GDM (CON: 6%, EXE: 7%, MOT: 7%, p = 1.000) or in birth weight (CON: 3630 (3024-3899), EXE: 3768 (3410-4069), MOT: 3665 (3266-3880), p = 0.083). CONCLUSIONS: Neither structured supervised exercise training nor motivational counselling on physical activity during pregnancy affected GWG or obstetric and neonatal outcomes compared to standard care. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03679130; 20/09/2018.

Time trends in mental health indicators during the initial 16 months of the COVID-19 pandemic in Denmark.

BACKGROUND: The COVID-19 pandemic and its associated national lockdowns have been linked to deteriorations in mental health worldwide. A number of studies analysed changes in mental health indicators during the pandemic; however, these studies generally had a small number of timepoints, and focused on the initial months of the pandemic. Furthermore, most studies followed-up the same individuals, resulting in significant loss to follow-up and biased estimates of mental health and its change. Here we report on time trends in key mental health indicators amongst Danish adults over the course of the pandemic (March 2020 - July 2021) focusing on subgroups defined by gender, age, and self-reported previously diagnosed chronic and/or mental illness. METHODS: We used time-series data collected by Epinion (N=8,261) with 43 timepoints between 20 March 2020 and 22 July 2021. Using a repeated cross-sectional study design, independent sets of individuals were asked to respond to the Copenhagen Corona-Related Mental Health questionnaire at each timepoint, and data was weighted to population proportions. The six mental health indicators examined were loneliness, anxiety, social isolation, quality of life, COVID-19-related worries, and the mental health scale. Gender, age, and the presence of previously diagnosed mental and/or chronic illness were used to stratify the population into subgroups for comparisons. RESULTS: Poorer mental health were observed during the strictest phases of the lockdowns, whereas better outcomes occurred during reopening phases. Women, young individuals (<34 yrs), and those with a mental- and/or chronic illness demonstrated poorer mean time-series than others. Those with a pre-existing mental illness further had a less reactive mental health time-series. The greatest differences between women/men and younger/older age groups were observed during the second lockdown. CONCLUSIONS: People with mental illness have reported disadvantageous but stable levels of mental health indicators during the pandemic thus far, and they seem to be less affected by the factors that result in fluctuating time-series in other subgroups.

Differences in insulin sensitivity in the partial remission phase of childhood type 1 diabetes; a longitudinal cohort study.

AIMS: Studies suggest that type 1 diabetes (T1D) contributes to impaired insulin sensitivity (IS). Most children with T1D experience partial remission but the knowledge regarding the magnitude and implications of impaired IS in this phase is limited. Therefore, we investigate the impact of IS on the partial remission phase. METHODS: In a longitudinal study of children and adolescents, participants were seen at three clinical visits during the first 14.5 months after diagnosis of T1D. Partial remission was defined as IDAA1c (HbA1c (%) + 4*daily insulin dose) ≤ 9. Beta-cell function was considered significant by a stimulated c-peptide > 300 pmol/L. Participants were characterized by (i) remission or non-remission and (ii) stimulated c-peptide levels above or below 300 pmol/L. IS, body mass index (BMI), total body fat, sex, age, pubertal status and ketoacidosis at onset were compared. RESULTS: Seventy-eight children and adolescents aged 3.3-17.7 years were included. At 14.5 months post-diagnosis, 54.5% of the participants with stimulated c-peptide > 300 pmol/L were not in partial remission. Participants not in remission had significant lower IS 2.5 (p = 0.032), and 14.5 (p = 0.022) months after diagnosis compared to participants in partial remission with similar c-peptide levels. IS did not fluctuate during the remission phase. CONCLUSIONS: A number of children and adolescents have impaired IS in the remission phase of paediatric T1D and are not in remission 14.5 months after diagnosis despite stimulated c-peptide > 300 pmol/L.

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia: The HypoDeg randomized, controlled, open-label, crossover trial.

AIM: To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Neonatal FeNO, risk factors, and respiratory morbidity in infants: A cohort study.

BACKGROUND: Respiratory symptoms in infancy are more common in premature infants. Nitric oxide (NO) is involved in prenatal and neonatal lung development. Measurement of exhaled NO is easy and well-tolerated by neonates. We investigated whether neonatal exhaled NO can be used to predict subsequent respiratory symptoms. Furthermore, we sought to determine prenatal and postnatal factors associated with increased respiratory symptom risk during the first year of life in premature and mature infants. METHODS: Tidal fractional exhaled NO (FeNO) was measured in a birth cohort (n = 135) of premature and mature infants, up to six times during the first month of life. Primary outcomes were troublesome respiratory symptoms (TRS) and doctor-diagnosed asthmatic bronchitis (AB) at 1 year of age. FINDINGS: The correlation between FeNO and TRS changed significantly in an age-dependent pattern in moderately premature infants (p = .02). Moderately premature infants with a low FeNO of 2 ppb on postnatal Day 3 had a 48% (95% confidence interval [CI]: 17%-80%) probability of TRS, compared with a probability of 12% (95% CI: 1%-64%) for otherwise similar infants with a FeNO of 11 ppb. Respiratory syncytial virus infection and parental smoking significantly increased the TRS risk in premature infants. Parental asthma and maternal antibiotic use during pregnancy significantly increased the TRS risk in mature infants. INTERPRETATION: An age-specific association between neonatal FeNO and respiratory symptoms was seen in moderately premature infants. TRS risk was associated with postnatal factors in premature and prenatal factors in mature infants.

Increased colon transit time and faecal load in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a bowel disorder involving abdominal pain or discomfort along with irregularity of stool form and passage frequency. The pathophysiology is poorly understood and seems to be multifactorial. Investigations of possible causes of IBS have included only a few colonic transit studies and no simultaneous determination of the colonic faecal content. AIM: To compare colon transit time and faecal load between IBS-patients and healthy control subjects. METHODS: The study included 140 patients with IBS, with a mean age of 50.0 years. The control group comprised 44 healthy persons with a mean age of 43.4 years, who were selected at random from the National Civil Register. Both the patient group and the control group underwent a marker study to measure colon transit time (CTT) and to calculate a faecal loading score. The patient group underwent treatment with a combined prokinetic regime, after which their CTT and faecal loading were reassessed. Analyses were performed to compare measurements between the control group and the patient group before and after treatment. RESULTS: Compared to healthy controls, IBS-patients exhibited a significantly prolonged mean CTT (45.48 h vs 24.75 h, P = 0.0002) and significantly greater mean faecal loading scores in all colonic segments (P < 0.001). Among IBS patients, we found no significant differences between the 48 h and 96 h radiographs. Among patients exhibiting increased CTT and faecal loading, approximately half exhibited a palpable mass in the right iliac fossa. After intervention with a prokinetic treatment, the mean CTT among IBS patients was reduced from 45.48 h to 34.50 h (P = 0.091), with the post-treatment CTT not significantly differing from the CTT among control subjects (P = 0.095). The faecal loading score among IBS patients did not significantly differ before and after treatment (P = 0.442). The post-treatment faecal loading score in IBS patients remained significantly higher compared to that in controls (5.3 vs 4.3, P = 0.014). After treatment, half of the IBS-patients were relieved of bloating, while the majority no longer experienced abdominal pain and achieved a daily consistent stool. CONCLUSION: IBS-patients exhibited prolonged CTT and heavier faecal loading. These assessments may aid in diagnosis. Faecal retention may contribute to IBS symptoms, which can be treated using a prokinetic regime.

The influence of active and passive air humidification on exhaled breath condensate volume.

Exhaled breath condensate (EBC) is safely collected in mechanically ventilated (MV) patients, but there are no guidelines regarding humidification of inhaled air during EBC collection. We investigated the influence of active and passive air humidification on EBC volumes obtained from MV patients. We collected 29 EBC samples from 21 critically ill MV patients with one condition of active humidification and four different conditions of non-humidification; 19 samples from 19 surgical MV patients with passive humidification and two samples from artificial lungs MV with active humidification. The main outcome was the obtained EBC volume per 100 L exhaled air. When collected with different conditions of non-humidification, mean [95% CI] EBC volumes did not differ significantly (1.35 [1.23; 1.46] versus 1.16 [1.05; 1.28] versus 1.27 [1.13; 1.41] versus 1.17 [1.00; 1.33] mL/100 L, p=0.114). EBC volumes were higher with active humidification than with non-humidification (2.05 [1.91; 2.19] versus 1.25 [1.17; 1.32] mL/100 L, p<0.001). The volume difference between these corresponded to the EBC volume obtained from artificial lungs (0.81 [0.62; 0.99] versus 0.89 mL/100 L, p=0.287). EBC volumes were lower for surgical MV patients with passive humidification compared to critically ill MV patients with non-humidification (0.55 [0.47; 0.63] versus 1.25 [1.17; 1.32] mL/100 L, p<0.001). While active humidification increases EBC volumes, passive humidification decreases EBC volumes and possibly influences EBC composition by other mechanisms. We propose that EBC should be collected from MV patients without air humidification to improve reproducibility and comparability across studies, and that humidification conditions should always be reported.

Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes.

BACKGROUND AND AIM: In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D. SUBJECTS AND METHODS: Ninety-nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino-terminal propeptide (P1NP) and the bone resorption marker C-terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C-peptide as representative of endogenous insulin production. RESULTS: OCN- and P1NP Z-scores were significantly decreased throughout the study, whereas CTX Z-scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z-score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C-peptide or IDAA1c at any visit. The individual change in CTX Z-score was negatively associated with the increase of IDAA1c (P = .030) independent of C-peptide decline (P = .034). CONCLUSION: Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.

Effect of Dosage of 17ß-Estradiol on Uterine Growth in Turner Syndrome-A Randomized Controlled Clinical Pilot Trial.

CONTEXT: Most Turner syndrome (TS) girls need exogenous estrogen treatment to induce puberty and normal uterine growth. After puberty, the optimal estrogen treatment protocol has not been determined. OBJECTIVE: To compare 2 doses of oral 17ß-estradiol on uterine size. DESIGN: A double-blind, 5-year randomized controlled clinical trial. SETTING: Ambulatory care. PARTICIPANTS: Twenty young TS women (19.2 ± 2.5 years, range 16.0-24.9) participated. Sixteen patients completed the study. No patients withdrew due to adverse effects. INTERVENTION: The lower dose (LD) group took 2 mg 17ß-estradiol/d orally and placebo. The higher dose (HD) group took 4 mg 17ß-estradiol/d orally. MAIN OUTCOME MEASURE(S): Uterine volume evaluated by transabdominal ultrasound yearly. RESULTS: Uterine size increased significantly more in the HD group compared with the LD group (P = 0.038), with a gain in uterine volume within the first 3 years of treatment of 19.6 mL (95% confidence interval [CI] = 4.0-19.0) in the HD group compared with 11.5 mL (95% CI = 11.2-27.9) in the LD group. The difference in 3-year gain was 8.1 mL (95% CI = 0.7-15.9). At the last visit, there were no significant differences in uterine volume between the groups. CONCLUSION: HD oral 17ß-estradiol induces a steeper increase in uterine volume within the first years of treatment compared with the LD. However, the uterine growth potential seems to be the same in most young TS women making the duration of treatment equally significant as estrogen dose, although a few TS women did not experience sufficient uterine growth on 2 mg of estradiol. CLINICALTRIALS.GOV: NCT00134745Abbreviations: BMI, body mass index; BSA, body surface area; DHEAS, dihydroepiandrosteronesulfate; HD, higher dose; HRT, hormone replacement therapy; LD, lower dose; TS, Turner syndrome; US, ultrasound.

Relationship between patient presentation and morphology of coronary atherosclerosis by quantitative multidetector computed tomography.

AIMS: Quantitative computed tomography (QCT) allows assessment of morphological features of coronary atherosclerosis. We aimed to test the hypothesis that clinical patient presentation is associated with distinct morphological features of coronary atherosclerosis. METHODS AND RESULTS: A total of 1652 participants, representing a spectrum of clinical risk profiles [787 asymptomatic individuals from the general population, 468 patients with acute chest pain without acute coronary syndrome (ACS), and 397 patients with acute chest pain and ACS], underwent multidetector computed tomography. Of these, 274 asymptomatic individuals, 254 patients with acute chest pain without ACS, and 327 patients with acute chest pain and ACS underwent QCT to assess coronary plaque volumes and proportions of dense calcium (DC), fibrous, fibro fatty (FF), and necrotic core (NC) tissue. Furthermore, the presence of vulnerable plaques, defined by plaque volume and tissue composition, was examined. Coronary plaque volume increased significantly with worsening clinical risk profile [geometric mean (95% confidence interval): 148 (129-166) mm3, 257 (224-295) mm3, and 407 (363-457) mm3, respectively, P < 0.001]. Plaque composition differed significantly across cohorts, P < 0.0001. The proportion of DC decreased, whereas FF and NC increased with worsening clinical risk profile (mean proportions DC: 33%, 23%, 23%; FF: 50%, 61%, 57%; and NC: 17%, 17%, 20%, respectively). Significant differences in plaque composition persisted after multivariable adjustment for age, gender, body surface area, hypertension, statin use at baseline, diabetes, smoking, family history of ischaemic heart disease, total plaque volume, and tube voltage, P < 0.01. CONCLUSION: Coronary atherosclerotic plaque volume and composition are strongly associated to clinical presentation.

Tidal breath eNO measurements in a cohort of unsedated hospitalized neonates-A method validation.

AIM: Exhaled Nitric oxide (eNO) is an inflammatory marker. In 2002 Hall et al. [J Appl Physiol. 92:59-66] established an infant eNO measurement method, fulfilling four criteria of feasibility: simple, non-invasive, without impact on the natural breathing pattern, and accounting for flow by NO output (V'NO). Although tidal breathing is accepted as an eNO measurement method in uncooperative patients, it is seldom used outside research labs. The variability and lack of validated methods have restrained from exploring the area in preterm and term neonates the last years. This study aimed to validate clinically feasible longitudinal online tidal eNO and V'NO in a real-life birth cohort of un-sedated, hospitalized preterm, and term neonates. METHOD: We included 149 newborns, GA 28-42 weeks. Each scheduled for six repeated, non-invasive, on-line eNO measurements with Ecomedics CLD 88sp and NO-free air. We used three 60-second-eNO measurements. The method was adapted to fit preterm and term neonates with unstable respiration, without excluding sighs and surrounding breaths. RESULT: Protocol measurements with a maximum mutual difference of 1 ppb succeeded in 85-99%, increasing with postnatal age. We performed mixed model analyses in three hierarchical measurement levels. Despite the irregular breathing of newborns, the predictions of individual eNO levels in the average infant was a 0.05 SD. Exhaled NO was flow-dependent (P = 0.028); V'NO but not eNO was associated with preterm birth (P < 0.001) and >24 h CPAP treatment (P = 0.0316). CONCLUSION: We validated clinically, non-invasive, online eNO measurements in neonates. The method was well tolerated and exhibited low subject-specific-prediction-variance and high success rates.

Multiplex polymerase chain reaction-based prognostic models in diffuse large B-cell lymphoma patients treated with R-CHOP.

We present a multiplex analysis for genes known to have prognostic value in an attempt to design a clinically useful classification model in patients with diffuse large B-cell lymphoma (DLBCL). Real-time polymerase chain reaction was used to measure transcript levels of 28 relevant genes in 194 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Including International Prognostic Index (IPI) as a variable in a penalized Cox regression, we investigated the association with disease progression for single genes or gene combinations in four models. The best model was validated in data from an online available R-CHOP treated cohort. With progression-free survival (PFS) as primary endpoint, the best performing IPI independent model incorporated the LMO2 and HLADQA1 as well as gene interactions for GCSAMxMIB1, GCSAMxCTGF and FOXP1xPDE4B. This model assigned 33% of patients (n = 60) to poor outcome with an estimated 3-year PFS of 40% vs. 87% for low risk (n = 61) and intermediate (n = 60) risk groups (P < 0·001). However, a simpler, IPI independent model incorporated LMO2 and BCL2 and assigned 33% of the patients with a 3-year PFS of 35% vs. 82% for low risk group (P < 0·001). We have documented the impact of a few single genes added to IPI for assignment in new drug trials.

Reproducibility of mass spectrometry based protein profiles for diagnosis of ovarian cancer across clinical studies: A systematic review.

The focus of this systematic review is to give an overview of the current status of clinical protein profiling studies using MALDI and SELDI MS platforms in the search for ovarian cancer biomarkers. A total of 34 profiling studies were qualified for inclusion in the review. Comparative analysis of published discriminatory peaks to peaks found in an original MALDI MS protein profiling study was made to address the key question of reproducibility across studies. An overlap was found despite substantial heterogeneity between studies relating to study design, biological material, pre-analytical treatment, and data analysis. About 47% of the peaks reported to be associated to ovarian cancer were also represented in our experimental study, and 34% of these redetected peaks also showed a significant difference between cases and controls in our study. Thus, despite known problems related to reproducibility an overlap in peaks between clinical studies was demonstrated, which indicate convergence toward a set of common discriminating, reproducible peaks for ovarian cancer. The potential of the discriminating protein peaks for clinical use as ovarian cancer biomarkers will be discussed and evaluated. This article is part of a Special Issue entitled: Proteomics: The clinical link.