Background Progressive respiratory failure is the leading cause of death in patients with severe COVID-19. Histopathological findings in acute severe COVID-19 are foremost based on post-mortem findings. On computed tomography (CT), acute COVID-19 pneumonia is characterized by ground-glass opacities (GGOs) and, later, by a crazy-paving pattern (CPP) and consolidations.Purpose To investigate if CT patterns corresponded to histopathological post-mortem findings.Material and Methods Eight patients were identified with a chest CT performed between testing positive for COVID-19 and death. CT images, histological slides, and medical records were retrospectively reviewed. The lungs were photographed during the gross investigation to ascertain the exact position of the tissue blocks in relation to the relevant anatomical structures. Each slide was compared side by side with the in vivo chest CT pattern on the corresponding site.Results At CT, the most predominant finding was GGOs, present in all eight cases. CPP was observed in 6/8 (75%) patients, and consolidation in 7/8 (87.5%) patients, both predominantly located in the lower lung zones. In 5 (62.5%) patients, so-called fibrotic-like changes were present. In four patients with CT angiogram, no findings of pulmonary thromboembolism were present. At autopsy, all patients demonstrated macroscopic consolidation, while pleural effusion was seen in 2 (25%) cases. Microscopically, edema was present in all cases, hyaline membranes in 7/8 (87.5%) cases, but no signs of acute interstitial inflammation were observed. Thromboembolic findings were evident in 4 (50%) patients, of whom two were negative on CT and 3 (37.5%) cases had fibrosis.Conclusion The results demonstrate a clear association between radiological signs of GGO, consolidation and features of organizing pneumonia to microscopical signs of edema and diffuse alveolar damage. However, fibrotic-like changes and thromboembolism in the small vessels had a poorer compliance.

Objectives:Artificial intelligence (AI) deep learning algorithms trained on non-contrast CT scans effectively detect and quantify acute COVID-19 lung involvement. Our study explored whether radiological contrast affects the accuracy of AI-measured lung opacities, potentially impacting clinical decisions. We compared lung opacity measurements from AI software with visual assessments by radiologists using CT pulmonary angiography (CTPA) images of early-stage COVID-19 patients. Methods:This prospective single-centre study included 18 COVID-19 patients who underwent CTPA due to suspected pulmonary embolism. Patient demographics, clinical data, and 30-day and 90-day mortality were recorded. AI tool (Pulmonary Density Plug-in, AI-Rad Companion Chest CT, SyngoVia; Siemens Healthineers, Forchheim, Germany) was used to estimate the quantity of opacities. Visual quantitative assessments were performed independently by 2 radiologists. Results:There was a positive correlation between radiologist estimations (r 2 = 0.57) and between the AI data and the mean of the radiologists' estimations (r 2 = 0.70). Bland-Altman plot analysis showed a mean bias of +3.06% between radiologists and -1.32% between the mean radiologist vs AI, with no outliers outside 2×SD for respective comparison. The AI protocol facilitated a quantitative assessment of lung opacities and showed a strong correlation with data obtained from 2 independent radiologists, demonstrating its potential as a complementary tool in clinical practice. Conclusion:In assessing COVID-19 lung opacities in CTPA images, AI tools trained on non-contrast images, provide comparable results to visual assessments by radiologists. Advances in knowledge:The Pulmonary Density Plug-in enables quantitative analysis of lung opacities in COVID-19 patients using contrast-enhanced CT images, potentially streamlining clinical workflows and supporting timely decision-making.

BACKGROUND:Persistent respiratory symptoms in COVID-19 patients have raised concerns about structural remodelling in the lung. We assessed structural changes and their correlation with reduced DLCO, eight months after discharge, in previously hospitalised COVID-19 patients. MATERIALS AND METHODS:An exploratory observational study was conducted on 26 male patients (mean age: 60 years, range: 50-69) previously hospitalised for COVID-19. CT scans, performed eight months post-discharge, were analysed using functional respiratory imaging (FRI) to assess lung structure and function. Analyses were made based on diffusion capacity for carbon monoxide (DLCO). RESULTS:Patients with low DLCO (≤75%; n = 9) exhibited a significantly lower proportion of small blood vessels with a cross-sectional area < 5 mm² compared to patients with normal DLCO (>75%; n = 17) (median (IQR) 56 (51-59) % vs. 60 (56-64) %, p = 0.008), as well as a reduced absolute volume of small vessels with a cross-sectional area < 5 mm² (129 (121-151) ml vs. 155 (132-175) ml, p = 0.025). Bronchial dilatation was more evident in the low DLCO group, with a higher ratio of airway volume to lobar volume (siVaw) (149 (138-165) % vs. 117 (93-132) %, p = 0.002). SiVaw showed a significant inverse relationship with DLCO (r = -0.56, p = 0.004, R² = 0.31). Lobar volumes were reduced in both DLCO groups, and more pronounced in the low DLCO group (72 (65-81) % vs. 90 (79-95) %, p = 0.001), as was total lung capacity (TLC) (73 (64-85) % vs. 92 (85-98) % of predicted, p = 0.003). FEV₁/FVC ratios were elevated in both groups, with a potential difference observed between the low and normal DLCO groups (110 (103-118) % vs. 105 (95-113) %, p = 0.074). CONCLUSIONS:We demonstrate long-term vascular and airway remodelling detected with FRI in previously hospitalised COVID-19 patients and highlight potential mechanisms underlying persistent pulmonary dysfunction and emphasise the need to investigate the underlying pathophysiology to identify potential individualised treatment strategies for this patient group.

Background:In this study, we combine proteomics with functional parameters and imaging to examine potential biomarkers that may identify patients at risk of developing persistent lung sequelae following coronavirus disease 2019 (COVID-19). Methods:We performed multiplex profiling of serum and collected clinical data from intensive care unit (ICU)-treated patients with COVID-19 (n=43) at 4 and 10 months post hospitalisation. Results:Four months post discharge, patients with COVID-19 demonstrated lower % predicted forced vital capacity (72.2% versus 113% (p<0.0001)) and % predicted forced expiratory volume in 1 s (74.5% versus 103% (p<0.0001)) compared with healthy controls. A persistent upregulation (versus healthy controls) of inflammatory and remodelling factors, including among others, Galectin-1 (Gal-1), C-X-C motif chemokine 13 (CXCL13), monocyte chemoattractant protein 3 (MCP-3) and matrix metalloproteinase 7 (MMP7), were observed. Patients with moderate to severe parenchymal involvement (>5% of lung tissue) on high-resolution computed tomography (HRCT) had higher levels of the proteins lysosomal associated membrane protein-3 (LAMP3) and MMP7 compared with patients with minor (<5%) or no findings on HRCT. Both proteins demonstrated consecutive associations to lung function and parenchymal involvement. Histological evaluation of LAMP3 in lung tissue confirmed LAMP3 localisation to alveolar type 2 cells in more preserved areas of the parenchyma. However, areas of remodelling were devoid of LAMP3 concurrent with the appearance of KRT5+ and KRT17+ basal cells. Conclusion:Despite functional and radiological improvements following COVID-19, persistent upregulation of inflammation and remodelling factors were observed. Similarities in the expression of LAMP3 in COVID-19 and idiopathic pulmonary fibrosis may suggest it as a potential biomarker for chronic lung damage.

Background: Children born with low birth weight may be at risk of developing the metabolic syndrome. Aim: Determine body composition and metabolic profile with focus on adipose tissue and leptin from childhood to young adulthood in a cohort of subjects born very preterm with LBW or term-born small for gestational age (SGA) compared to controls. Methods: This follow-up cohort study included 82 adults (57% women), mean age 21 (range 19-22) years. Seventy-four (90%) of these had taken part in a pre-pubertal study at age 9 years and were re-examined. The adult cohort comprised of subjects born very preterm (<30 gestational weeks) (n= 31) (preterm), born SGA (n=24) and full-term normal-weight controls (n= 27). Demographics including target height were collected. Adipose tissue was estimated by impedance. Fasting levels of glucose, c-peptide, leptin, insulin, insulin growth factor (IGF) binding protein (BP)-1, IGF-I and glucagon were determined. Results: Preterm women weighed less (p<0.01) and had lower height SDS (p<0.05) compared with control women at follow-up. Preterm women had lower total adipose tissue percentage (24 (20–27) vs 29 (25–32) %, p=0.037), and trunk fat mass (19 (15–23) vs 26 (22–30)%, p=0.029) compared with control women, not seen in preterm men. Glucose or insulin did not differ between groups, but mean C-peptide was higher in SGA women compared with preterm women (p<0.05). Leptin levels did not differ between groups (p=0.86). Leptin was closely correlated with total adipose content in men (r= 0.79, p< 0.001) and in women (r= 0.84, p< 0.001). Leptin adjusted for adipose tissue was higher in all preterm compared with controls (p=0.017). In multiple regression analyses, 78% of the leptin variability was explained by adipose tissue percentage, insulin and gender (p<0.0001, n=76). In preterm men IGF-I was strongly correlated with adipose tissue percentage (r=0.77, p<0.001). Conclusion: In young adulthood, preterm women weigh less, were shorter and had lower adipose tissue percentage, and all preterm had higher leptin levels adjusted for adipose tissue. We speculate that the higher leptin levels in relation to adipose tissue in preterm might serve as protection to enhance insulin sensitivity. The higher C-peptide could indicate peripheral insulin resistance in SGA women. IGF-I could be of special importance to adipose tissue in preterm men.

BackgroundFew studies consider both radiological and functional outcomes in COVID-19 survivors treated in the intensive care unit (ICU). We investigated clinical findings and pulmonary abnormalities on chest computed tomography (CT) and compared outcomes of severe versus mild-moderate acute respiratory distress syndrome (ARDS) on long-term follow-up.MethodsThis longitudinal cohort study included 118 COVID-19 patients (median age, 58 years; 79% men). Thoracic CT scans were performed 4, 10, and 22 months after hospital discharge. Two independent blinded radiologists analyzed the 10 months scans and scored the radiology findings semi-quantitatively, as no/minor versus widespread opacities [low-radiology opacity grade (ROG) versus high-ROG]. ARDS severity was based on the PaO2/FiO2 ratio. The 6 min walk test (6MWT) was performed after 3 and 9 months, and lung diffusion capacity for carbon monoxide (DLCO) and lung volume measurement after 9 and 15 months. Dynamic spirometry was done at all time points. Residual symptoms and health-related quality-of-life (HRQL) were evaluated using validated questionnaires.ResultsAt 10 months, most patients (81/118; 69%) were classified as high-ROG, of which 70% had severe ARDS during hospitalisation; 69% of those with mild-moderate ARDS also had high-ROG. Patients with high-ROG had longer ICU stay and lower PaO2/FiO2 during hospitalisation (p < 0.01). At 9 months follow-up, patients with high-ROG had smaller lung volumes as % of predicted values [mean (±CI): 80 (77–84) vs. 93 (88–98) (p < 0.001)], lower DLCO as % of predicted values [74 (70–78) vs. 87 (82–92) (p < 0.001)], lower oxygen saturation during 6MWT (p = 0.02), and a tendency to more severe dyspnoea (p = 0.07), but no difference was found in HRQL compared with no/minor ROG (p = 0.92). A higher opacity score was related to lower DLCO at follow-up (r = −0.48, p < 0.001, Spearman rank test). Severe ARDS patients had slightly more severe fatigue at 9 months compared to mild–moderate, but no differences in dyspnoea or lung function at follow-up. Fibrotic-like changes were found in 93% of patients examined with CT scans at 2 years (55/118; 47%). Severe ARDS could predict widespread opacities (ROG > 25%) in most patients at follow-up at 10 months (AUC 0.74).ConclusionResidual radiological abnormalities in ICU-treated COVID-19 patients, evaluated for up to 2 years, relate to persisting symptoms and impaired lung function, demanding careful follow-up regardless of ARDS severity at hospitalisation.

Purpose To study the prevalence of primary adrenal tumors and adrenal metastases in patients with neuroendocrine neoplasms (NENs) and describe these in detail. NENs can be further divided into neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC).Methods A review of medical files was conducted for all patients who underwent a 68Gallium-DOTATOC-PET/CT during 2010-2023 or adrenalectomy during 1999-2023 at the Karolinska University Hospital.Results In total, 68Gallium-DOTATOC-PET/CT was performed on 1750 individuals with NEN, among whom 12 (0.69%) had adrenal tumors. Of these, 9 (0.51%) were NEN metastases. Out of 1072 adrenalectomies, 4 (0.37%) showed evidence of NEN metastases. Thus, 16 patients with NEN exhibited adrenal tumors. The adrenal tumors were found on average 5 years after the NEN diagnosis and 19% of the adrenal tumors with simultaneous NEN were benign. Few had all adrenal hormones measured. None had an adrenal insufficiency nor an adrenal biopsy. Another synchronous metastasis was found in 69% at the time of the adrenal tumor discovery. During the median 2-year follow-up, 38% of the subjects had deceased (with the exclusion of individuals presenting supposedly benign adrenal tumors 31%) all due to tumor complications. A comparison between individuals identified through 68Gallium-DOTATOC-PET/CT and those who underwent adrenalectomy revealed a higher prevalence of NETs in the former group and NECs in the latter group.Conclusion Adrenal primary tumors and adrenal metastases are infrequent occurrences in patients with NEN. Most cases involved the presence of NEN metastasis upon the initial discovery of adrenal tumors. The overall prognosis was found to be favorable.

BACKGROUND AND OBJECTIVE:Information on the incidence of adrenal trauma and its association with other injuries is limited. Our objective was to study the incidence of adrenal haemorrhage, its association with other injuries, clinical parameters, and long-term outcomes.PATIENTS AND MEASUREMENTS:All patients treated for severe abdominal trauma (Level 1) at Karolinska University Hospital, Solna, between January 1, 2013 and December 31, 2018 were included. Patients with a radiological picture of adrenal haematoma were selected. The injury severity score (ISS) was analysed in the entire cohort. Data were collected from the electronic medical files.RESULTS:In total, 1.7% (n = 29/1743) was affected by adrenal trauma. Right adrenal trauma (n = 20/29;69%) was more common than left (n = 6/29;21%, p < 0.01), and 10% were bilateral (n = 3/29). There was no difference in volume in right versus left adrenal trauma [(median 13 (interquartile range (IQR) (7-15) versus 8 (5-13)] ml, p = 0.30). ISS was 23.4 (17-43) in adrenal haematoma patients, higher compared with other trauma patients 16 (8-27) (n = 1714)(p < 0.001). Rib fractures, pneumothorax, and liver lacerations were the three most common findings in association with adrenal trauma. The underlying cause in 48% of the cases was falling from height (≥3 m). Biochemical data demonstrated normal sodium and potassium levels while the lowest haemoglobin level was 72 g/l. At follow-up, 4 (2-6) years after the trauma, except for three patients who died as in-patients, all other persons were still living. None seemed to have adrenal insufficiency.CONCLUSIONS:Adrenal trauma is rare and does not seem to be associated with clinical features of adrenal insufficiency, even if the bleeding is bilateral.

This Swedish study evaluated whether the severity of retinopathy of prematurity (ROP) in extremely preterm infants was related to their overall outcome in young adulthood. We followed 39 individuals born between 1988 and 1993 at less than 28 gestational weeks, included in the Stockholm Neonatal Project. A total of 19 were treated for severe ROP, and 20 had no or mild ROP. They were assessed for general cognitive abilities and mental health at 18 years of age and compared with 23 term-born controls. Visual acuity was examined at 21-25 years. They were asked about their education and everyday life. The 19 individuals with severe treated ROP had lower visual acuity and higher risk for intellectual deficits, cerebral palsy and neuropsychiatric diagnoses than those with no or mild ROP and the term controls. Three were visually impaired, none were blind. They were less physically active than the other groups and had more problems finding their way around. However, nine were at university. Young adults treated for severe ROP had more problems resulting from cerebral dysfunction than those with no or mild ROP and term-born controls. Retinal and brain pathologies in the extremely preterm infant constitute different expressions of neurovascular disease.

Purpose: Severe COVID-19 is associated with inflammation, thromboembolic disease, and high mortality. We studied factors associated with fatal outcomes in consecutive COVID-19 patients examined by computed tomography pulmonary angiogram (CTPA). Methods: This retrospective, single-center cohort analysis included 130 PCR-positive patients hospitalized for COVID-19 [35 women and 95 men, median age 57 years (interquartile range 51–64)] with suspected pulmonary embolism based on clinical suspicion. The presence and extent of embolism and parenchymal abnormalities on CTPA were recorded. The severity of pulmonary parenchymal involvement was stratified by two experienced radiologists into two groups: lesions affecting ≤50% or >50% of the parenchyma. Patient characteristics, radiological aspects, laboratory parameters, and 60-day mortality data were collected. Results: Pulmonary embolism was present in 26% of the patients. Most emboli were small and peripheral. Patients with widespread parenchymal abnormalities, with or without pulmonary embolism, had increased main pulmonary artery diameter ( p < 0.05) and higher C-reactive protein ( p < 0.01), D-dimer ( p < 0.01), and troponin T ( p < 0.001) and lower hemoglobin ( p < 0.001). A wider main pulmonary artery diameter correlated positively with C-reactive protein ( r = 0.28, p = 0.001, and n = 130) and procalcitonin. In a multivariant analysis, D-dimer >7.2 mg/L [odds ratio (±95% confidence interval) 4.1 (1.4–12.0)] and ICU stay were significantly associated with embolism ( p < 0.001). The highest 60-day mortality was found in patients with widespread parenchymal abnormalities combined with pulmonary embolism (36%), followed by patients with widespread parenchymal abnormalities without pulmonary embolism (26%). In multivariate analysis, high troponin T, D-dimer, and plasma creatinine and widespread parenchymal abnormalities on CT were associated with 60-day mortality. Conclusions: Pulmonary embolism combined with widespread parenchymal abnormalities contributed to mortality risk in COVID-19. Elevated C-reactive protein, D-dimer, troponin-T, P-creatinine, and enlarged pulmonary artery were associated with a worse outcome and may mirror a more severe systemic disease. A liberal approach to radiological investigation should be recommended at clinical deterioration, when the situation allows it. Computed tomography imaging, even without intravenous contrast to assess the severity of pulmonary infiltrates, are of value to predict outcome in COVID-19. Better radiological techniques with higher resolution could potentially improve the detection of microthromboses. This could influence anticoagulant treatment strategies, preventing clinical detoriation.

AIM:This Swedish study evaluated whether the severity of retinopathy of prematurity (ROP) in extremely preterm infants was related to their overall outcome in young adulthood. METHODS:We followed 39 individuals born between 1988 and 1993 at less than 28 gestational weeks, included in the Stockholm Neonatal Project. A total of 19 were treated for severe ROP, and 20 had no or mild ROP. They were assessed for general cognitive abilities and mental health at 18 years of age and compared with 23 term-born controls. Visual acuity was examined at 21-25 years. They were asked about their education and everyday life. RESULTS:The 19 individuals with severe treated ROP had lower visual acuity and higher risk for intellectual deficits, cerebral palsy and neuropsychiatric diagnoses than those with no or mild ROP and the term controls. Three were visually impaired, none were blind. They were less physically active than the other groups and had more problems finding their way around. However, nine were at university. CONCLUSION:Young adults treated for severe ROP had more problems resulting from cerebral dysfunction than those with no or mild ROP and term-born controls. Retinal and brain pathologies in the extremely preterm infant constitute different expressions of neurovascular disease.

Objective microRNAs (miRNAs) associated with metabolic risk have never been extensively investigated in SGA subjects. The aim of the current study was to evaluate miRNAs in SGA and AGA subjects and their relationships with the metabolic status and growth. Design and methods A prospective longitudinal case-control study was performed in 23 SGA with postnatal catch-up growth and 27 AGA subjects evaluated at the age of 9 and 21 years. Circulating levels of miR-122-5p, miR-16-5p, miR-126-3p, and miR-486-5p were assessed by qPCR. Results SGA subjects were shorter both at 9 and at 21 years. No significant differences in insulin like growth factors and metabolic profile were found with the exception of basal glycemia at 9 years. miRNA levels did not differ between SGA and AGA subjects, at 9 and 21 years. miR-16-5p and miR-126-3p levels were higher at 9 than at 21 years. In SGA subjects, miR-122-5p at 9 years was inversely related to adiponectin levels at 21 years and miR-486-5p at 9 years was inversely related to whole-body insulin sensitivity at 9 years and directly related to Hb1Ac at 21 years. Regression analyses showed no predictive value of miRNAs for growth parameters in neither SGA nor AGA subjects. Conclusions SGA with postnatal catch-up growth did not show any difference in metabolic risk markers or miRNA circulating levels compared to AGA controls in childhood and young adulthood. miR-122-5p during childhood could identify SGA subjects at higher risk of developing insulin resistance and, eventually, type 2 diabetes in adulthood but further studies are needed to confirm it.

OBJECTIVE:Growth factors in the blood of very preterm infants may reflect growth and contribute to the understanding of early development. We investigated postnatal levels of insulin-like growth factors (IGFs) in infants born very preterm and related them to early growth development. DESIGN:Blood samples were analyzed weekly for IGF-I, IGF-II, IGF binding protein (BP)-1, IGFBP-3, and acid-label subunit (ALS). METHODS:73 children born very preterm (gestational age (GA) <32 weeks) were divided according to their gender-specific birth weight standard deviation score (SDS) into either appropriate for GA (AGA) or small for GA (SGA). Fifty-two (71%) and forty-three (59%) infants completed follow-up with anthropometry at approximately 3 years and at 5 years of age respectively. Thirty-six subjects (49%) had blood sampling for IGF-I and IGFBP-3 measurements up to 3 years of age. RESULTS:IGF-I, IGFBP-3, and ALS levels increased in all groups from week 31 to week 36, with generally lower levels in the SGAs, with a concomitant lower growth velocity. Postnatal ALS was strongly associated with IGF-I and IGFBP-3 in boys, girls and AGA infants. IGF-II was higher in earlier born preterms (GA < 27 weeks) at postmenstrual ages 27.5-29.9 weeks compared with SGAs and late GA (GA ≥ 27 weeks) preterms (p < .0001). IGF-II, in contrast to IGF-I, did not differ between SGAs and AGAs at weeks 31-36. Mean IGFBP-1 was highest in the SGAs compared to AGAs at mean week 28,5 and 31 (p = .001) and IGFBP-1 levels were elevated in relation to IGF-I in the SGAs at that period. At follow-up, the increase in IGF-I between week 31 and 33.5 was a significant positive determinant of height SDS at 3 and 5 years of age in forward multiple regression analysis, independent of target height. CONCLUSION:This is the first study to investigate postnatal ALS levels in preterm infants. In very preterm infants, IGF-II is less affected by size at birth during early postnatal weeks compared with IGF-I. Early elevated IGFBP-1 might protect the SGA infants from an intense metabolic rate. Our results indicate that anabolic and metabolic processes during weeks 31-36 predicts later height.

In Sweden, about 7000 infants are born preterm every year, before 37 weeks, and they account for 4%-5% of residents under the age of 18. There is an ongoing debate about how preterm birth affects health outcomes during the early postnatal weeks and in adult life. For example, preterm birth has been associated with a higher incidence of cardiovascular, metabolic and mental health issues in adulthood.1 In this issue of Acta Paediatrica, Forsum et al2 used weight and air-displacement plethysmography to investigate the fat mass and fat-free mass of 188 preterm children born at 23.2-36.9 weeks of gestation, including 73 born very and extremely preterm before week 32. These are called the early preterm group in the paper, and any aged 32 weeks or more are called late preterm. The authors compared them with 253 age-matched full-term controls when they reached four years of age. The findings confirmed other pre-pubertal studies that infants born before 32 weeks tended to weigh less and be shorter than full-term controls.3-5 The early preterm girls in the Forsum et al study had a significantly lower body mass index (BMI) than the girls in the full-term control group, but not the early preterm boys. Both the early preterm girls and boys had less fat mass than the corresponding controls. The early preterm girls also had less fat-free mass than their full-term peers. The late preterm girls and boys did not differ from the full-term controls with regard to fat mass. Gestational age was a weak, but significant, positive predictor of the investigated growth variables at follow-up in girls, but not in boys.2 One of the strengths of the Forsum et al study, apart from the relatively large cohort, was that it was conducted systematically and methodically, with little variations in age between the preterm and full-term groups at follow-up. In air-displacement plethysmography, body composition is estimated from density, which is then divided into fat mass and fat-free mass. Total body mass thus equals fat mass plus fat-free mass. Fat-free mass comprises skeletal muscle, organs, bone and supporting tissues. Height is the most important factor in fat-free mass. Air-displacement plethysmography is considered the method of choice for measuring body composition in children, and it is more readily accessible than dual-energy X-ray absorptiometry (DEXA), which is mostly used for measuring bone mineral density. However, DEXA measures bone mineral content directly, which means that it eliminates one of the major sources of fat-free mass variability in the two-compartment model. Several studies of pre-pubertal children have found similar results to Forsum et al, as the authors pointed out. Huke et al used impedance analysis to evaluate fat mass in 116 preterm born children when they reached 5-7 years of age and found that they were shorter, weighed less, had lower BMIs and had less fat mass than full-term controls.3 Another study investigated 200 preterm children, including those born very preterm and late preterm, using DEXA. After adjusting for height, the preterm group had less fat mass, but similar fat-free mass, than the full-term group. Being female strongly predicted elevated fat mass.4 Gianni et al5 found that preterm born children had lower fat masses, heights and weights at five years of age than full-term controls. Our smaller study of four-year-olds differed to Forsum et al as the preterm and full-term groups had similar BMIs, weights and adjusted height standard deviation scores at follow-up.6 After adjusting for height, the preterm group had a greater fat mass and lower fat-free mass than the full-term subjects. All these findings lead us to conclude that preterm subjects have a favourable fat mass body composition during pre-pubertal years, when they remain thin and short. In 1992, Hales and Barker proposed the thrifty-phenotype hypothesis7 for the aetiology of type 2 diabetes and suggested that low-birthweight infants had impaired beta-cell growth. As long as the individual remained undernourished, the need for insulin was small. However, if the infant ate too much and experienced rapid catch-up growth, the reduced beta-cell function could trigger diabetes. The debate continues whether a low birthweight, per se, or weight gain in infancy can predict a worse metabolic outcome in adulthood. In accordance with this, a study of preterm subjects who experienced rapid catch-up growth throughout infancy showed a later risk of increased intra-abdominal adiposity, and altered, decreased insulin sensitivity.8 In that study, preterm infants who were born small for gestational age seemed to have the greatest risk. Forsum et al2 found that the early preterm girls had a mean birthweight z-score of −0.93 ± 1.4. That group probably included infants born appropriate for gestational age and small for gestational age, below the 5th percentile or below—2 standard deviations (SD). At a mean age of 4.4 years, the early preterm girls were relatively lighter and shorter than average, with a mean weight of—1 SD compared to the reference value for Swedish children of the same age. At follow-up, some early preterm girls weighed<−2 SD of the reference weight. Z-scores for growth variables at follow-up were not presented. Thus, it was difficult to estimate adjusted catch-up growth variables. Overall, all the preterm girls appeared to have had a more distinct height catch-up, from birth to four years, compared to the preterm boys. However, the question remains about whether the different preterm groups differed in height SD score (SDS) relative to their predicted target height SDS at follow-up? One way to estimate this would be to calculate the difference in height SDS in relation to target height SDS. Further studies might focus on preterm infants born small for gestational age and the possible effects of catch-up or lack of catch-up growth on the studied parameters. Early nutrition may also be of importance for later body composition. Formula feeding or breastfeeding during infancy might affect body composition differently, as indicated by magnetic resonance scans at term-equivalent age in very preterm infants.9 Forsum et al did not provide information about early nutritional intake in the different groups. It would also have been interesting to have data on certain metabolic features, like the glucose or fasting insulin levels of these children. A study by de Jong found that two-year-old subjects born preterm had lower body mass indexes (BMI) and lower fat mass, but higher glucose levels, than full-term subjects.10 What will the effects of puberty be on these preterm groups? At the age of 20, DEXA showed that a large group of individuals born preterm had greater total fat mass and greater lean body masses, adjusted for height SDS, than full-term individuals.11 Therefore, it will be important to follow the Forsum et al cohort to evaluate the impact of puberty. The association between fat distribution per se and low birthweight is of interest. The waist-to-hip ratio or the waist circumference can shed some light on fat distribution. Excess visceral fat has been associated with insulin resistance. In preterm children, central adiposity and possible correlations with prematurity have shown different results.3, 5 The finding by Forsum et al that gestational age was only correlated to body composition markers in girls, but not boys, could be due to gender differences, a hidden impact of being born small for gestational age, and/or, a difference in catch-up growth between very low-birthweight girls and boys. Moreover, this gender difference might change over time. An alternative, but rather unlikely, theory is that gender variations might be explained by different brown adipose tissue content. However, in adult subjects born preterm, both sexes exhibited brown adipose tissue.12 Leptin is a circulating hormone derived from adipocytes that are released in proportion to the adipose tissue mass. Lack of adipose tissue results in a leptin deficiency, severe hyperglycaemia and intractable diabetes. Thus, to a certain extent, the effects of fat mass could be beneficial. In the Forsum et al2 study, both full-term and preterm girls tended to have larger amounts of fat relative to their weights than boys. We found similar results at 9 years of age, where leptin levels were slightly higher in girls than in boys. Leptin levels were strongly correlated with the BMI SDS, but this was not observed in adult women born preterm.13 It is possible that pre-pubertal females who are born small for gestational age and exhibit high leptin levels, relative to their BMI SDS, may be protected from later hyperglycaemia.13 Subjects may have different abilities to compensate for adverse metabolic outcomes, independent of body composition. The leptin-to-adipose tissue ratio might be particularly important in preterm subjects with a risk of hyperglycaemia in adulthood. Thus, the development of type 2 diabetes might be related to a low leptin-to-adipose tissue ratio.14 Frequent follow-up of growth variables in preterm children is important. In relation to life expectancy, cardiovascular outcomes probably have a greater impact than body composition, although the latter probably does play a minor role. A bigger threat may come from a combination of growth failure and behavioural and eating disorders.15 Forsum et al are to be congratulated for describing a large study population that, hopefully, will be further monitored and can provide a future bank of knowledge. None. Anna Kistner

Abstract Background: Brown adipose tissue (BAT) is present and functions to dissipate energy as heat in young adults and can be assessed using magnetic resonance imaging (MRI) to estimate the voxel fat fraction, i.e. proton density fat fraction (PDFF). It is hypothesized that subjects born preterm or small for gestational age (SGA) may exhibit disrupted BAT formation coupled to metabolic factors. Our purpose was to assess the presence of BAT in young adults born extremely preterm or SGA in comparison with controls. Methods: We studied 30 healthy subjects (median age, 21 years): 10 born extremely preterm, 10 full term but SGA and 10 full term with a normal birth weight (controls). We utilized an MRI technique combining multiple scans to enable smaller echo spacing and an advanced fat-water separation method applying graph cuts to estimate B0 inhomogeneity. We measured supraclavicular/cervical PDFF, R2*, fat volume, insulin-like growth factor 1, glucagon, thyroid stimulating hormone and the BAT-associated hormones fibroblast growth factor 21 and irisin. Results: The groups did not significantly differ in supraclavicular/cervical PDFF, R2*, fat volume or hormone levels. The mean supraclavicular/cervical PDFF was equivalent between the groups (range 75–77%). Conclusions: Young adults born extremely preterm or SGA show BAT development similar to those born full term at a normal birth weight. Thus, the increased risk of cardiovascular and metabolic disorders in these groups is not due to the absence of BAT, although our results do not exclude possible BAT involvement in this scenario. Larger studies are needed to understand these relationships.

Background: Adults born preterm are at risk of developing cardiovascular morbidities. Objective: The aim of this study was to evaluate the relationship between retinopathy of prematurity (ROP) and blood pressure (BP) and salivary cortisol levels during adulthood. Methods: Sixty-nine subjects (mean age 22.6 years) were included. Subjects were adults who were: (a) ex-preterm infants with severe ROP (n = 22), born at gestational age (GA) <30 weeks with a birth weight (BW) <1,000 g, (b) ex-preterm infants with no/mild ROP (n = 21), born at GA <28 weeks with a BW <1,000 g, or (c) full-term controls (n = 26). Anthropometric data, office BP, ambulatory BP, and morning and evening salivary cortisol were analyzed. Results: As adults, ex-preterm infants with severe ROP had on average 7.4 mm Hg higher systolic office BP than those with no/mild ROP (p = 0.019) and controls (p = 0.007). A high cortisol level, tall height, and severe ROP were independent predictors of higher ambulatory systolic BP during adulthood in forward stepwise regression analysis, independent of GA. Conclusion: Our results indicate that preterm infants with severe abnormal retinal vascular development during the neonatal period may be at an increased risk for increased BP during adulthood. We found no differences between those with no/mild ROP as infants and controls with regard to BP data.

Preterm children are at risk of developing increased blood pressure (BP). We evaluated possible associations between BP, early insulin‐like growth factor‐1 (IGF‐1) and IGF‐binding protein‐1 (IGFBP‐1) levels and retinopathy of prematurity (ROP) in preterm children.