IGFBP-1 and IGFBP-2 are associated with a decreased pulse-wave velocity in young, healthy adults.

BACKGROUND AND AIMS: In healthy, young adults we analyzed a panel of cardiovascular disease related proteins in plasma and compared them with the vascular health of the subjects. The aim was to identify proteins with a relationship to the early atherosclerotic process in healthy individuals. METHODS: We employed the proximity extension assay from OLINK proteomics to analyze 92 cardiovascular disease (CVD) related proteins on 833 subjects (men and women, ages 18-26). The women were further divided into an estrogen-using group and non-users. Protein expression was analyzed using principal component analysis (PCA). The following vascular examinations were performed: Pulse-wave velocity (PWV), augmentation index (AIX), carotid-intima media thickness (cIMT). RESULTS: Three principal components were obtained using PCA to analyze the protein expression. None of the obtained principal components correlated significantly with AIX or cIMT. One of the components, explaining 6% of the total variance of the data, was significantly correlated with PWV. Upon examination of the proteins with the highest factor loadings on this component independently in a multivariable model, adjusting for established CVD risk biomarkers, insulin-like growth factor-binding protein 1 (IGFBP-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) were found to independently, negatively correlate with PWV. Among the established risk factors included in the multivariable model, age was significantly and adversely correlated with all vascular measurements. CONCLUSIONS: In this population of healthy, young adults, groups of CVD related proteins correlate with PWV, but not AIX or cIMT. This group of proteins, of which IGFBP-1 and IGFBP-2 were independently, negatively correlated in a multivariable model with PWV, could have benificial effects on vascular stiffness. The robust association between age and PWV, AIX and cIMT provide insight into the impact of aging on the vasculature, which is detectable even in a population of young, healthy, non-smoking individuals of ages spanning only 8 years.

Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm.

Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.

Body fat percentage is more strongly associated with biomarkers of low-grade inflammation than traditional cardiometabolic risk factors in healthy young adults - the Lifestyle, Biomarkers, and Atherosclerosis study.

The primary aim was to appraise the relationship between body fat percentage and the inflammatory markers C-reactive protein (CRP) and orosomucoid in a population of young, non-smoking, healthy, Swedish adults, without any chronic diseases. A secondary aim was to compare whether these associations differed between the women using estrogen contraceptives and those who did not. We assessed the association in linear regression models between body fat percentage based on a bio-impedance measurement and plasma concentrations of CRP and orosomucoid in men and women aged 18-26 years, n = 834. Statistically significant associations were found between body fat percentage and both biomarkers of inflammation, with ß coefficients of 0.30 (95% CI 0.24-0.37) and 0.28 (0.22-0.35) for CRP and orosomucoid, respectively (p < .001). Adjustment for established risk factors marginally lowered the effects sizes (partial betas, 0.28 and 0.20, respectively), while the strong statistically significant associations remained. In the female cohort, estrogen and non-estrogen using subpopulations did not significantly differ in the correlations between body fat percentage and the inflammatory biomarkers, even adjusted for established cardiometabolic risk factors. In conclusion, in healthy young adults, higher levels of body fat percentage are associated with elevations in plasma biomarkers of inflammation, suggesting that a systemic inflammatory process, promoting atherosclerosis, may commence already at this early stage in life. CRP and orosomucoid plasma concentrations differed between users and non-users of estrogen contraceptives, but both subgroups showed similar correlations between increasing body fat percentage and increasing plasma concentrations of the biomarkers of inflammation.

Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis.

PURPOSE: Neuroendocrine tumours (NET) are uncommon and may be localized in many different places in the body. Traditional imaging has mainly been performed with CT and somatostatin receptor scintigraphy (SRS). Recently, it has become possible to use somatostatin receptor PET/CT (SMSR PET) instead, which might improve diagnostic quality. To evaluate the diagnostic quality of SMSR PET we performed a meta-analysis as an update of a previous study published in 2012. METHODS: A literature search was performed searching MEDLINE, Embase and five other databases with a combination of the expressions "PET", "positron emission tomography", "neuroendocrine" and "NET". The search was updated to 31 December 2012. Studies were selected which evaluated the sensitivity and specificity of SMSR PET for NET in the thorax or abdomen with a study size of at least eight patients. The methodological quality of the included studies was evaluated with QUADAS-2. RESULTS: Eight studies fulfilled the inclusion criteria and were selected for final analysis, and 14 articles from a previous meta-analysis were added for a total of 22 articles. A total of 2,105 patients were included in the studies, an increase from 567 in the previous meta-analysis. The pooled sensitivity was 93 % (95 % CI 91 - 94 %) and specificity 96 % (95 % CI 95 - 98 %). The area under the summary ROC curve was 0.98 (95 % CI 0.95 - 1.0). In the previous meta-analysis the pooled sensitivity was 93 % (95 % CI 91 - 95 %) and specificity 91 % (95 % CI 82 - 97 %). CONCLUSION: SMSR PET has good diagnostic performance for evaluation of NET in the thorax and abdomen, better than SRS which has been the previous standard method. This meta-analysis gives further support for switching to SMSR PET.

Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?

It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence.

Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: A case report and a review of the literature.

BACKGROUND: A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body. METHODS: Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma. RESULTS: Her serum Zn concentration was 105-133 µmol/L. Zn levels in her hair (102 µg/g), nail (90 µg/g) and urine (3-12 µmol/L; 20-80 µg/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin. CONCLUSION: Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

Could carbon monoxide and bilirubin be friends as well as foes of the body?

Endogenous carbon monoxide (CO) production was first described 60 years ago. CO is a by-product of the metabolism of haeme to biliverdin. This, in turn, becomes bilirubin. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against reactive oxygen species (ROS). The studies have focused on bilirubin as a biomarker of arterial disease. Recently the potential of CO as a therapeutic agent has been explored. This review assesses the current state of evidence and sets the data in the context of whether CO is an endogenous signalling molecule, a marker of vascular disease and, whether, together with bilirubin, CO could be a potential therapeutic agent.

Response to Owen, Singh and Kirschner - Prenatal testing is a necessary part of antenatal care.

Everyone wants a healthy baby. No sane person sets out to have a sick or disabled child. It is the duty and joy of healthcare to help to increase the chances of a happy event. Until delivery, healthcare must do its utmost to decrease the risk of a sick child or a child with a disability being born.

Non-invasive prenatal testing: Special interest groups vs women's autonomy.

Non-invasive prenatal testing (NIPT) is moving the goalposts for the detection of genetic disorders such as Down Syndrome (DS). NIPT not only misses fewer cases than first trimester combined screening, but also has fewer false positive results. Unlike with neural tube defect (NTD) where screening to detect affected pregnancies was welcomed, NIPT for trisomy has met with surprising resistance. This paper argues that special interest groups have been allowed to usurp influence beyond what is balanced in the discussions, at the expense of the fight against sex selection. The fear of parents of children with DS, that their children's rights might be devalued, must not trump the autonomy of pregnant women to decide what is best for their own family and what they can cope with emotionally and financially. Society, however, must ensure that resources for caring for those with DS and other disabilities remain adequate. Here, recent articles are also reviewed.

Half a century and more of PhD theses by published papers: Comment on: "Bringing the doctoral thesis by published papers to the Social Sciences and the Humanities: A quantitative easing? A small study of doctoral thesis submission rules and practice in two disciplines in the UK" by John Rigby and Barbara Jones in Scientometrics published online 15-May-2020.

The recent article by Rigby and Jones in Scientometrics (15-May-2020) again draws attention to basing PhD-theses on published works, in their case introducing the system into the Social Sciences and Humanities. In this short communication we endeavour to provide additional information that is essential for this debate.

Pulse wave velocity, augmentation index, and carotid intima-media thickness are each associated with different inflammatory protein signatures in young healthy adults: The lifestyle, biomarkers and atherosclerosis study.

BACKGROUND AND AIMS: We aimed to identify plasma protein biomarkers related to inflammation that correlated with physiological measurements of vascular function and structure in healthy individuals. METHODS: We used the OLINK proteomics panel, which measures 92 inflammatory proteins, in 834 young, healthy non-smokers (ages 18-26). Principal component analysis (PCA) was employed to identify patterns of proteins. The following measurements were used: pulse-wave velocity (PWV), carotid intima-media thickness (cIMT) and augmentation index (AIX). Established cardiovascular risk factors were included in multivariable models. RESULTS: PCA showed four principal components (PC 1, PC 2, PC 3, PC 4). PC 3, comprising proteins related to hemostasis, was significantly and inversely correlated with PWV. Among the proteins with the highest factor loadings on PC 3, uPA was negatively correlated with PWV in multivariable regression models. AIX was significantly correlated with PC 2, comprising inflammatory cytokines. Among the proteins with the highest factor loadings on PC 2, interleukin-6 was significantly correlated with AIX in the multivariable model. cIMT was significantly correlated with PC 4, comprising proteins related to chemotaxis. Among the proteins with the highest factor loadings on PC 4, fractalkine was significantly correlated with cIMT in the multivariable model. CONCLUSIONS: In young, healthy individuals, OLINK inflammatory proteins correlated with measures of vascular status. Each of the three measures PWV, AIX, and cIMT, which target different parts of the vasculature, correlated with its own specific protein signature, indicating that different subsets of inflammatory mediators affect different parts of the vasculature and are detectable already in young healthy adults.

Declarations of conflict of interest are still inadequate.

Declaration of conflicts of interest (COI, understood mainly as financial) in medical publications is long established. Most journals refer only to the guidelines of the International Committee of Medical Journal Editors (ICMJE) but not to those of the WAME (World Association of Medical Editors). We surveyed 17 journals and found only one (BJOG), which explicitly mentioned "religious interest" as an example of a possible COI and one other journal included "personal belief" (Journal of Obstetrics and Gynaecology of India) as a COI. Of the other 15 journals, 10 used the ICJME as their COI model. They were the general journals, NEJM, JAMA, Lancet, BMJ and JIM (Journal of Internal Medicine); the pediatric/neonatology journals Pediatrics and Journal of Pediatrics (this also mentions WAME) but not Acta Paediatrica, which mentions COPE; the obstetrics/gynaecology journals AJOG and IJOG; and the British Journal of Haematology but not Blood, which uses the American Society of Hematology's own COI model. Neither EJOG, JOG, IndianObs Gyn, nor J Obstet Gynaecol India clearly specified a COI model. Yet the ICMJE COI guidelines fail to include involvement in religious and/or secular groups which take sides on the subject being discussed, while the WAME guidelines specifically do so. Instead the ICMJE uses the vaguer phrase "intellectual beliefs". The actual ICJME COI-form does not itemise religion. To maintain their scientific credibility, medical journals must start requiring disclosure of such ties. A typical example where current ICMJE rules fall short is the ongoing heated debates over the ethics of prenatology and of physician assisted suicide.

Ethical stumbling blocks in uncovering folate deficiency as a preventable cause of spina bifida.

The year 2016 witnessed the anniversaries of several key events related to the prevention of neural tube defects (NTD) with folate supplementation. However, the road leading up to this achievement was full of stumbling blocks, both in terms of research ethics and researcher ethics. First, the decisions of ethics review boards differed with respect to allowing placebo groups in folate trials, thus reducing the level of evidence obtained from the earliest studies. Second, statisticians insisted on analysing the outcome of a trial by intention-to-treat - which turned out to be non-significant - rather than by treatment received, which was statistically significant. Third, the recognition of positive results was stymied by the reluctance of some researchers to recognise and quote others' contributions. All this needlessly delayed the recognition of the NTD-preventive effects of folate by a decade. The story of the prevention of NTD thus offers insights into research inadequacies that have the potential to impede the advance of medical science, with the ethical aspects having the most immediate impact. Efficient ethics review boards play a major role worldwide and if they play safe, they may risk disallowing high-quality studies of great public health import.

Does bilirubin protect against developing diabetes mellitus?

After 25 years of evaluating bilirubin as a possible protective agent in neonatal and cardiovascular disease, interest has moved on to a exploring a possible protective role in diabetes mellitus (DM). This review finds conflicting prospective data for a protective relationship though there are retrospective, case-controlled data, that can only show association, which is not causality. Only prospective studies can show causality. Also, it would appear that the underlying biochemical assumptions do not readily translate from the animal to the human setting. Given that many factors impact on circulating bilirubin levels, it is not surprising that a clear-cut answer is not available; the jury is still out. Any relationship between DM and bilirubin might relate to intermediates in bilirubin metabolism, including relationships involving the genes for the enzymes participating in those steps. Nevertheless, the pursuit of bilirubin in disease causation is opening new avenues for research and if it is established that serum bilirubin can predict risks, much will have been achieved. The answer may have to come from molecular genetic analyses.

Is bilirubin a marker of vascular disease and/or cancer and is it a potential therapeutic target?

Normal aerobic metabolism is associated with reactive oxygen species (ROS) that can damage cellular macromolecules. Analogous free radicals are formed by exposure to ionizing radiation and many dietary products are considered to contain free radical generators. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against ROS. The studies have focused on bilirubin as a biomarker of arterial disease. This review assesses the current state of evidence and sets the data in context. There is no definitive evidence from prospective studies of a causal protective effect from bilirubin in arterial disease or that various genetic polymorphisms, (particularly the 7/7 UGT1A1 repeat polymorphism) impacts coronary artery disease. There is no definitive evidence that high bilirubin levels confer protection against cancer. There is some preliminary evidence that bilirubin may have a protective effect in lung disease and stroke, but the reports have yet to be confirmed. The role of various genotypes of UGT1A1 and HMOX1, if any, in cancer is unclear.