Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes.

Haptoglobin-related protein (Hpr) is a plasma protein with high sequence similarity to haptoglobin (Hp). Like Hp, Hpr also binds hemoglobin (Hb) with high affinity, but it does not bind to the Hb-Hp receptor CD163 on macrophages. The Hpr concentration is markedly lower than Hp in plasma and its regulation is not understood. In the present study, we have developed non-crossreactive antibodies to Hpr to analyze the Hpr concentration in 112 plasma samples from anonymized individuals and compared it to Hp. The results show that plasma Hpr correlated with Hp concentrations (rho = 0.46, p = .0001). Hpr accounts for on average 0.35% of the Hp/Hpr pool but up to 29% at low Hp levels. Furthermore, the Hpr concentrations were significantly lower in individuals with the Hp2-2 phenotype compared to those with the Hp2-1 or Hp1-1 phenotypes. Experimental binding analysis did not provide evidence that Hpr associates with Hp and in this way is removed via CD163. In conclusion, the Hpr concentration correlates to Hp concentrations and Hp-phenotypes by yet unknown mechanisms independent of CD163-mediated removal of Hb-Hp complexes.

Re-evalution of the measurement of haptoglobin in human plasma samples.

Haptoglobin (Hp) is an abundant plasma protein scavenging hemoglobin (Hb) via CD163 on macrophages. This process consumes Hp, which therefore negatively correlates to hemolysis. However, exact measurements of Hp plasma levels are complicated by different phenotypes (Hp1-1, Hp2-1, and Hp2-2) forming different oligomeric states with differences in immunoreactivity. In addition, humans have an immune-cross-reactive Hp-related protein. In the present study, we developed Hp-specific monoclonal antibodies for an accurate Hp analysis of the different Hp phenotypes in a panel of 112 anonymous samples from hospitalized individuals subjected to routine Hp immunoturbidimetric measurements. The data revealed immunoturbidimetry as a reliable method in most cases but also that the use of non-phenotype-specific calibrators leads to substantial bias in the measurement of the Hp-concentration, non at least in Hp1-1 individuals. Furthermore, analysis of the Hb-dependence of the CD163 interaction with Hp1-1 and Hp2-2 showed that a higher 'cost-effectiveness' in the consumption of dimeric Hp1-1 versus multimeric Hp phenotypes is a likely contribution to the observed differences in the plasma levels of the Hp phenotypes. In conclusion, the determination of Hp phenotype and the use of phenotype-specific calibrators are essential to obtain a precise estimate of the Hp level in healthy and diseased individuals.

Platelet parameters and leukocyte morphology is altered in COVID-19 patients compared to non-COVID-19 patients with similar symptomatology.

In this nested case-control study, we evaluated haematological and morphological parameters of hospitalised patients with real-time polymerase chain reaction verified COVID-19 infection compared to patients with similar symptomatology but without COVID-19 infection. Seventy-four COVID-19 positive and 228 COVID-19 negative patients were evaluated with routine haematological parameters. Severe disease was defined as death and/or need of intensive care treatment. Twenty-seven COVID-19 positive and 18 COVID-19 negative patients were furthermore included for morphological evaluation using smear examination. Significant differences were found for platelet indices and white blood cell parameters. Thus, platelet count and plateletcrit was lower in COVID-19 patients, whilst mean platelet volume, platelet distribution width, and platelet large cell ratio was significantly higher than in non-COVID-19 patients. Leukocyte, neutrophil, immature granulocyte, lymphocyte, monocyte, eosinophil, and basophil count was lower in COVID-19 patients. No significant differences were found for red blood cell count, haemoglobin, haematocrit or mean corpuscular haemoglobin for COVID-19 versus non-COVID-19 patients. COVID-19 patients with a severe disease course had higher levels of immature granulocytes, but lower lymphocyte and platelet counts compared to patients with non-severe COVID-19. In terms of morphology, 14.8% of COVID-19 patients had a normal smear examination, compared to 83.3% of non-COVID-19 patients. Hypogranulated neutrophils were more frequent in COVID-19 patients (p < .001), but non-COVID-19 patients had higher levels of reactive lymphocytes, compared to COVID-19 patients. In conclusion, several haematological morphological abnormalities are more frequent in patients with COVID-19 disease, and several findings indicate that platelets play a fundamental role in the pathophysiology of the disease.

Verification of the hemolysis index measurement: imprecision, accuracy, measuring range, reference interval and impact of implementing analytically and clinically derived sample rejection criteria.

Automated spectrophotometric measurement of hemolysis index (HI) allows rapid and cost-effective assessment of hemolysis interference. We evaluated the analytical performance of HI on two different platforms. Further, the impact of implementing analytically and clinically derived sample rejection criteria was investigated. Precision profiles were established, and analytical error was assessed by comparison with the reference method for hemoglobin measurement on Architect c8000/c16000 (Abbott) and Cobas c702 (Roche Diagnostics) instruments. The impact of a more analyte-specific cut off based on analytical and biologival variation was examined for five hemolysis-sensitive plasma analyses according to European recommendations. Lastly, a reference interval was established for the HI on Cobas, using the CLSI C28A3c nonparametric method. Imprecision for HI of 0.6-3.0 % for Architect and 1.5-4.5 % for Cobas was considered acceptable, which also applied for trueness in the measuring tange > 2 g/L. If cutoffs based on analytical and biological variation were used to manage results from hemolyzed samples, more potassium, LDH, conjugated bilirubin and phosphate results would be suppressed. Considering RCV only LDS remained sensitive to hemolysis. The Cobas-based HI reference interval was established to 0.01-0.16 g/L. Thorough verification of the HI on two different clinical chemistry analyzers reveals acceptable analytical performance. HI cutoffs suggested by manufacturers may be optimized by clinical laboratories using analytical and/or biological variation. A reference interval for the HI analysis is relevant as the analysis has been suggested as a diagnostic tool in the assessment of in vivo hemolysis.

Iron deficiency in healthy 18-month-old Danish children is associated with no oral iron supplementation in infancy and prolonged exclusive breast-feeding.

Fe deficiency (ID) defined as plasma ferritin <12 µg/l is associated with delayed cognitive development in early childhood and increased incidence of infections; however, the longitudinal association between early-life factors and ID in 18-month-old children in Denmark is unknown. The present study aimed to determine the prevalence of ID and to describe risk factors associated with ID in healthy 18-month-old Danish children. Blood samples, anthropometric measurements and self-reported questionnaire data had been obtained in the birth cohort, Odense Child Cohort. The questionnaires were modified from those used in the Danish National Birth Cohort. Plasma ferritin and C-reactive protein in venous, non-fasting samples were analysed in the final sample size of 370 children after exclusion of seventy-nine children due to chronic disease, acute infection, C-reactive protein >10 mg/l, twin birth or prematurity. Associations with ID were analysed by logistic regression, adjusting for sex, maternal education, duration of partial breast-feeding and current intake of milk, fish and meat. Overall, fifty-six children had ID (15·1 %). Factors associated with increased risk were exclusive breast-feeding beyond 4 months (OR 5·97; 95 % CI 1·63, 21·86) and no intake of oral Fe supplements from 6 to 12 months (OR 3·99, 95 % CI 1·33, 11·97. Duration of partial breast-feeding and current diet was not associated with ID. In conclusion, the ID prevalence was 15·1 %, and both exclusive breast-feeding beyond 4 months and no intake of oral Fe supplements from 6 to 12 months were associated with increased risk of ID in 18-month-old children.

Exome sequencing of contralateral breast cancer identifies metastatic disease.

Women with contralateral breast cancer (CBC) have significantly worse prognosis compared to women with unilateral cancer. A possible explanation of the poor prognosis of patients with CBC is that in a subset of patients, the second cancer is not a new primary tumor but a metastasis of the first cancer that has potentially obtained aggressive characteristics through selection of treatment. Exome and whole-genome sequencing of solid tumors has previously been used to investigate the clonal relationship between primary tumors and metastases in several diseases. In order to assess the relationship between the first and the second cancer, we performed exome sequencing to identify somatic mutations in both first and second cancers, and compared paired normal tissue of 25 patients with metachronous CBC. For three patients, we identified shared somatic mutations indicating a common clonal origin thereby demonstrating that the second tumor is a metastasis of the first cancer, rather than a new primary cancer. Accordingly, these patients all developed distant metastasis within 3 years of the second diagnosis, compared with 7 out of 22 patients with non-shared somatic profiles. Genomic profiling of both tumors help the clinicians distinguish between true CBCs and subsequent metastases.

Recent infections are associated with decreased risk of rheumatoid arthritis: a population-based case-control study.

OBJECTIVES: Do recent infections affect the risk of rheumatoid arthritis (RA)? METHODS: We used the population-based case-control study EIRA (N=6401) on incident RA and healthy controls, matched for sex, age, calendar period and area of residence. Gastroenteritis, urinary tract infection, genital infection, prostatitis, sinusitis, tonsillitis and pneumonia during the 2 years before inclusion in the study were investigated. Conditional logistic regression was used to calculate OR, adjusting for smoking and socioeconomic status. RESULTS: Infections in the gastrointestinal and urogenital tract before clinical onset were associated with a lowered risk of RA: gastroenteritis (OR=0.71 (95% CI 0.63 to 0.80)), urinary tract infections (OR=0.78 (95% CI 0.68 to 0.90)) and genital infections (OR=0.80 (95% CI 0.64 to 1.00)), while a non-significant association of similar magnitude was observed for the less common prostatitis (OR=0.64 (95% CI 0.38 to 1.08)). In contrast, no associations were observed for sinusitis, tonsillitis or pneumonia. CONCLUSIONS: Gastrointestinal and urogenital infections, but not respiratory infections, are associated with a significantly lowered risk of RA. The results indicate that infections in general do not affect the risk for RA, but that certain infections, hypothetically associated with changes in the gut microbiome, could diminish the risk.

Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis.

AIM: To investigate whether overweight/obesity at diagnosis affects the chances of decrease in disease activity and pain in early rheumatoid arthritis (RA). METHOD: We investigated incident RA cases from the population-based Epidemiological Investigation of risk factors for Rheumatoid Arthritis (EIRA) study (2006-2009, N=495) with clinical follow-up in the Swedish Rheumatology Quality Register. At diagnosis, 93% received disease-modifying antirheumatic drugs (DMARDs) (86% methotrexate). The odds of achieving a good response according to the DAS28-based European League Against Rheumatism (EULAR) criteria, low disease activity (DAS28<3.2), remission (DAS28<2.6) or pain remission (visual analogue scale ≤20 mm) at 3-months and 6-months follow-up, were calculated using logistic regression, adjusting for potential confounders. RESULTS: Significant dose-response relationships were found between Body Mass Index (BMI) and change of disease activity as well as pain at both time points. Patients with BMI ≥25 had 51% lower odds of achieving low disease activity (odds ratio (OR=0.49 (95% CI 0.31 to 0.78)) and 42% lower odds of remission (OR=0.58 (95% CI 0.37 to 0.92)) at the 6-months visit, compared to normal-weight patients. This effect was also present at 3 months, where we also found a 43% decreased odds of pain remission (OR=0.57 (95% CI 0.37 to 0.88)). No effect modification was found for anti-citrullinated protein antibody (CCP)-status, sex, prednisolone treatment or DAS28 at diagnosis. CONCLUSIONS: Overweight at diagnosis significantly decreases the chance of achieving good disease control during the early phase of RA.

Patients with regular physical activity before onset of rheumatoid arthritis present with milder disease.

OBJECTIVES: Physical activity has been shown to decrease inflammatory markers; here we investigate the effect on the clinical presentation of rheumatoid arthritis (RA). METHODS: We used the cases from the population-based EIRA study (N=617), followed in the Swedish Rheumatology Quality Register, calculating the odds of having above median level of 28-joint disease activity score (DAS28), physician assessment, pain (visual-analogue scale (VAS), VAS-pain) and activity limitation (health assessment questionnaire (HAQ)) at diagnosis, as an effect of physical activity 5 years before diagnosis, investigated both in categories and dichotomised. RESULTS: Dose-response relationships were seen for all measures; the higher the level of physical activity, the lower the likelihood of having outcome measure above median. Further, regular physical activity associated with 42% reduced odds of having DAS28 above median (OR=0.58 (95% CI 0.42 to 0.81)). Effects were similar for VAS-pain (OR=0.62 (95%CI 0.45 to 0.86)) and physician assessment (OR=0.67 (95%CI 0.47 to 0.95)) but not for HAQ. Statistically significant effects were also found both for the combined objective components and the combined subjective components of DAS28. CONCLUSIONS: Physically active individuals seem to present with milder RA, which adds to the evidence of beneficial effects of physical activity on inflammatory diseases. The observation should be important for both health professionals and individuals seeking to reduce their risk.

European multicenter analytical evaluation of the Abbott ARCHITECT STAT high sensitive troponin I immunoassay.

BACKGROUND: International recommendations highlight the superior value of cardiac troponins (cTns) for early diagnosis of myocardial infarction along with analytical requirements of improved precision and detectability. In this multicenter study, we investigated the analytical performance of a new high sensitive cardiac troponin I (hs-cTnI) assay and its 99th percentile upper reference limit (URL). METHODS: Laboratories from nine European countries evaluated the ARCHITECT STAT high sensitive troponin I (hs-TnI) immunoassay on the ARCHITECT i2000SR/i1000SR immunoanalyzers. Imprecision, limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ) linearity of dilution, interferences, sample type, method comparisons, and 99th percentile URLs were evaluated in this study. RESULTS: Total imprecision of 3.3%-8.9%, 2.0%-3.5% and 1.5%-5.2% was determined for the low, medium and high controls, respectively. The lowest cTnI concentration corresponding to a total CV of 10% was 5.6 ng/L. Common interferences, sample dilution and carryover did not affect the hs-cTnI results. Slight, but statistically significant, differences with sample type were found. Concordance between the investigated hs-cTnI assay and contemporary cTnI assay at 99th percentile cut-off was found to be 95%. TnI was detectable in 75% and 57% of the apparently healthy population using the lower (1.1 ng/L) and upper (1.9 ng/L) limit of the LoD range provided by the ARCHITECT STAT hs-TnI package insert, respectively. The 99th percentile values were gender dependent. CONCLUSIONS: The new ARCHITECT STAT hs-TnI assay with improved analytical features meets the criteria of high sensitive Tn test and will be a valuable diagnostic tool.

Change of mammographic density predicts the risk of contralateral breast cancer--a case-control study.

INTRODUCTION: Mammographic density is a strong risk factor for breast cancer, but it is unknown whether density at first breast cancer diagnosis and changes during follow-up influences risk of non-simultaneous contralateral breast cancer (CBC). METHODS: We collected mammograms for CBC-patients (cases, N = 211) and unilateral breast cancer patients (controls, N = 211), individually matched on age and calendar period of first breast cancer diagnosis, type of adjuvant therapy and length of follow-up (mean follow-up time: 8.25 years). The odds of CBC as a function of changes of density during follow-up were investigated using conditional logistic regression, adjusting for non-dense area at diagnosis. RESULTS: Patients who experienced ≥10% absolute decrease in percent density had a 55% decreased odds of CBC (OR = 0.45 95% CI: 0.24 to 0.84) relative to patients who had little or no change in density from baseline to first follow-up mammogram (mean = 1.6 (SD = 0.6) years after diagnosis), whereas among those who experienced an absolute increase in percent density we could not detect any effect on the odds of CBC (OR = 0.83 95% CI: 0.24 to 2.87). CONCLUSION: Decrease of mammographic density within the first two years after first diagnosis is associated with a significantly reduced risk of CBC, this potential new risk predictor can thus contribute to decision-making in follow-up strategies and treatment.

Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer.

We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population-based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 1976-2005 and 750 patients in South Sweden 1977-2005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.27-2.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.40-3.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM-stage [OR 2.16 (95% CI 1.13-4.11)] and higher histological grade [OR = 2.00 (95% CI 1.08-3.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy.

Angiotensin II regulates microRNA-132/-212 in hypertensive rats and humans.

MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are emerging as key regulators in cardiovascular development and disease. MiRNAs are involved in cardiac hypertrophy, heart failure and remodeling following cardiac infarction; however, miRNAs involved in hypertension have not been thoroughly investigated. We have recently reported that specific miRNAs play an integral role in Angiotensin II receptor (AT1R) signaling, especially after activation of the Gαq signaling pathway. Since AT1R blockers are widely used to treat hypertension, we undertook a detailed analysis of potential miRNAs involved in Angiotensin II (AngII) mediated hypertension in rats and hypertensive patients, using miRNA microarray and qPCR analysis. The miR-132 and miR-212 are highly increased in the heart, aortic wall and kidney of rats with hypertension (159 ± 12 mm Hg) and cardiac hypertrophy following chronic AngII infusion. In addition, activation of the endothelin receptor, another Gαq coupled receptor, also increased miR-132 and miR-212. We sought to extend these observations using human samples by reasoning that AT1R blockers may decrease miR-132 and miR-212. We analyzed tissue samples of mammary artery obtained from surplus arterial tissue after coronary bypass operations. Indeed, we found a decrease in expression levels of miR-132 and miR-212 in human arteries from bypass-operated patients treated with AT1R blockers, whereas treatment with ß-blockers had no effect. Taken together, these data suggest that miR-132 and miR-212 are involved in AngII induced hypertension, providing a new perspective in hypertensive disease mechanisms.

The Influence of Physical Mixing and Impregnation on the Physicochemical Properties of Pine Wood Activated Carbon Produced by One-Step ZnCl2 Activation.

In this study, two different sample preparation methods to synthesize activated carbon from pine wood were compared. The pine wood activated carbon was prepared by mixing ZnCl2 by physical mixing, i.e., "dry mixing" and impregnation, i.e., "wet mixing" before high temperature carbonization. The influence of these methods on the physicochemical properties of activated carbons was examined. The activated carbon was analyzed using nitrogen sorption (surface area, pore volume and pore size distribution), XPS, density, Raman spectroscopy, and electrochemistry. Physical mixing led to a slightly higher density carbon (1.83 g/cm3) than wet impregnation (1.78 g/cm3). Raman spectroscopy analysis also showed that impregnation led to activated carbon with a much higher degree of defects than physical mixing, i.e., ID/IG = 0.86 and 0.89, respectively. The wet impregnated samples also had better overall textural properties. For example, for samples activated with 1:1 ratio, the total pore volume was 0.664 vs. 0.637 cm3/g and the surface area was 1191 vs. 1263 m2/g for dry and wet mixed samples, respectively. In the electrochemical application, specifically in supercapacitors, impregnated samples showed a much better capacitance at low current densities, i.e., 247 vs. 146 F/g at the current density of 0.1 A/g. However, the physically mixed samples were more stable after 5000 cycles: 97.8% versus 94.4% capacitance retention for the wet impregnated samples.

Comparison of plasma total carbon dioxide and standard hydrogen carbonate in a hospital laboratory setting.

BACKGROUND: Studies comparing venous total carbon dioxide (tCO2) and standard hydrogen carbonate (HCO3-(P,st)) has shown diverse results, and it is debatable whether these two parameters can be used interchangeably for workup of acid-base disorders in a hospital setting. METHOD: All patients with an HCO3-(P,st) requisition from any department at Odense University Hospital between 11th May 2021 and 1st June 2021 had tCO2 and HCO3-(P,st) analysed simultaneously. TCO2 was measured on Cobas® 8000, c702 module, while HCO3-(P,st) was calculated based on measurements on ABL835 Flex. RESULTS: From 1210 patients, mean (standard deviation (SD)) was 22.9 (3.7) mmol/L for tCO2 and 22.5 (2.9) mmol/L for HCO3-(P,st). TCO2 range was 10.1-42.3 mmol/L and 11.7-41.4 mmol/L for HCO3-(P,st). Linear regression showed that tCO2 (mmol/L) = -2.90 + 1.15 × HCO3-(P,st) (mmol/L) with R2 = 0.81. Bias (mean (SD) difference) between tCO2 and HCO3-(P,st)) was 0.4 (1.7) mmol/L with a -5.0-9.6 mmol/L range. Limits of agreement was -2.90-3.70 mmol/L. Comparison of classification within, above or below reference interval for tCO2 and HCO3-(P,st) showed that 984 samples (81%) retained their classification. Only one sample (0.1%) would be severely misclassified (outside the respective reference intervals) if HCO3-(P,st) was considered the gold standard. Of the samples investigated, 46.1% had a mean difference between tCO2 and HCO3-(P,st) of 0-1 mmol/L and 30.3% had 1.1-2.0 mmol/L. CONCLUSIONS: Our results indicate that venous tCO2 and venous HCO3-(P,st) can be used interchangeably in a hospital setting for workup of acid-base disorders.

Prognostic implications of estrogen receptor pattern of both tumors in contralateral breast cancer.

Estrogen receptor (ER) status is important for breast cancer survival, it is however unclear how prognosis of contralateral breast cancer (CBC) is affected by ER-status of the two tumors. We conducted a large, population-based study of ER-status of both tumors in CBC patients and its influence on prognosis. The cohort consisted of all women diagnosed with CBC in Stockholm, Sweden during 1976-2005, with information on ER-status from medical records (N = 933). Prognosis was modeled as incidence rates of distant metastasis via Poisson regression. The proportion of CBCs with both cancers of the same ER-status was significantly larger than expected by chance. For synchronous (simultaneous) cancers the prognosis was significantly affected by the combined ER-status of both tumors (p = 0.01). Compared to unilateral breast cancer patients the incidence rate ratio (IRR) for patients with double ER-positive tumors was 1.25 (95 % CI: 0.88-1.76), for ER-discordant tumors 2.19 (95 % CI: 1.18-4.08) and for double ER-negative tumors 3.95 (95 % CI: 1.77-8.81). For metachronous (non-simultaneous) cancers, women with double ER-positive tumors had similarly bad prognosis (IRR = 2.95; 95 % CI: 2.39-3.64) as women with double ER-negative tumors (IRR = 2.88; 95 % CI: 1.83-4.52). Both shorter time span between first and second cancer and endocrine therapy for the first cancer further worsened prognosis of women with double ER-positive metachronous CBC. For synchronous CBC patients, ER-pattern of both tumors is an important prognosticator, while among metachronous CBC patients, double ER-positive tumors confer equally bad prognosis as double ER-negative cancers. Our results indicate that this might be due to endocrine therapy resistance.

Diagnostic work-up of contralateral breast cancers has not improved over calendar period.

Women who have been treated for breast cancer are typically followed up with regular mammography and palpation, with the aim of detecting recurrences and contralateral breast cancer (CBC). This study aims to investigate if the diagnostic work-up of breast cancer patients has improved over the last 25 years and resulted in earlier diagnoses of CBC. Two population-based cohorts were used; all CBCs in Sweden 1976-2004 (n: 2932), and all CBCs in Stockholm, Sweden, 1976-2005 (n: 626), both cohorts with a maximum of 3 years between the two cancers. Synchronous CBC was defined as two cancers <3 months apart, the remainder was defined as metachronous CBC. We calculated the odds ratio of being diagnosed synchronously, relative to metachronously, using logistic regression, adjusting for whether the second cancer was detected through clinical work-up or not. The odds of synchronous CBC were significantly increased: 1.27 (95% CI, 1.13-1.42) per 5-year period, compared to metachronous, and was not affected by detection mode, but seemed to be explained by adjuvant therapy. The proportion of CBCs detected by clinical work-up did not increase over the study period, and the mean size of the second tumor remained constant. We found an increase in the proportion of synchronous CBCs compared to metachronous, over calendar period, a change that was not associated with clinical work-up, but with adjuvant therapy. This study gives no indications that any improvement in diagnostic work-up of CBC have occurred over the last 25 years.

Laboratory Tests and Outcome for Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019 (COVID-19) and poses substantial challenges for healthcare systems. With a vastly expanding number of publications on COVID-19, clinicians need evidence synthesis to produce guidance for handling patients with COVID-19. In this systematic review and meta-analysis, we examine which routine laboratory tests are associated with severe COVID-19 disease. CONTENT: PubMed (Medline), Scopus, and Web of Science were searched until March 22, 2020, for studies on COVID-19. Eligible studies were original articles reporting on laboratory tests and outcome of patients with COVID-19. Data were synthesized, and we conducted random-effects meta-analysis, and determined mean difference (MD) and standard mean difference at the biomarker level for disease severity. Risk of bias and applicability concerns were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. SUMMARY: 45 studies were included, of which 21 publications were used for the meta-analysis. Studies were heterogeneous but had low risk of bias and applicability concern in terms of patient selection and reference standard. Severe disease was associated with higher white blood cell count (MD, 1.28 ×109/L), neutrophil count (MD, 1.49 ×109/L), C-reactive protein (MD, 49.2 mg/L), lactate dehydrogenase (MD, 196 U/L), D-dimer (standardized MD, 0.58), and aspartate aminotransferase (MD, 8.5 U/L); all p < 0.001. Furthermore, low lymphocyte count (MD -0.32 × 109/L), platelet count (MD -22.4 × 109/L), and hemoglobin (MD, -4.1 g/L); all p < 0.001 were also associated with severe disease. In conclusion, several routine laboratory tests are associated with disease severity in COVID-19.

Birth Season and Infection Risk Among Children Under 5 Years Old: A Study of Hospital Admissions and Short Message Service-reported Symptoms at Home.

BACKGROUND: The season in which a child is born may affect the immune system development and thereby influence the risk of infections. In this study, we examined the associations between birth season and the risk of hospital admission or symptoms associated with a wide range of infections. METHODS: This study is a prospective cohort study of 2434 children with an average follow-up of 3.5 years. Admission data were obtained from the Danish National Patient Registry. Via short message service (SMS) questionnaires, 1279 families reported symptoms of infections in a 1-year period. RESULTS: Of the 2434 children, 639 (26.3%) were admitted to the hospital, and the children experienced on average 64.4 days with symptoms of infection within 1 year. There was no association between birth season and hospital admissions due to all infectious causes [incidence rate ratio (IRR) = 0.89; 95% confidence interval (CI), 0.65-1.22; P = 0.471]. However, children born in the fall had a higher IRR for admission due to all infectious causes when excluding admissions within the first year of life. Winter- and spring-born children had lower IRRs for admission due to gastrointestinal infections than summer-born children, but this association was alone present when admissions within the first year of life were included. The short message service-survey showed significantly lower IRRs for any symptom of infection among winter-born (IRR = 0.85; 95% CI, 0.75-0.96; P = 0.009) and fall-born children (IRR = 0.88; 95% CI, 0.78-0.99; P = 0.033) in comparison with summer-born children. CONCLUSIONS: Birth season was not associated with hospital admission due to all infectious causes within the first 5 years of age; however, fall-birth was associated with a higher IRR for admissions due to all infectious causes after the first year of life. The association between birth season and admissions due to gastrointestinal infections was only seen when including children admitted under the age of one. Being born in fall or winter was associated with a decreased IRR for number of days with any symptom of infection registered at home.

Prenatal Exposures to Perfluoroalkyl Acids and Associations with Markers of Adiposity and Plasma Lipids in Infancy: An Odense Child Cohort Study.

BACKGROUND: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy. OBJECTIVES: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy. METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth (n=613) and at 3 months (n=602) and 18 months (n=503) of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months (n=262) and 18 months (n=198) of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models. RESULTS: PFNA and PFDA were associated with higher BMI SDS [adjusted ß=0.26; 95% confidence interval (CI): 0.03, 0.49 and ß=0.58; 95% CI: -0.03, 1.19, respectively, for 1-ng/mL increases] and ponderal index SDS (ß=0.36; 95% CI: 0.13, 0.59 and ß=1.02; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for 1-ng/mL PFDA, ß=0.40; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months (ß=1.06; 95% CI: 0.08, 2.03) (n=83). DISCUSSION: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184.