Fetal origins-A life cycle model of health and aging from conception to death.

The fetal origins hypothesis suggests that health and nutrition shocks in utero are causally related to health deficits in old age. It has received considerable empirical support, both within epidemiology and economics but so far it has not been integrated into a life cycle theory of human aging and longevity. The present study shows that the health deficit model, based on the frailty index developed in gerontology, generates shock amplification consistent with the hypothesis. In order to discuss human health over the life cycle from conception to death, we develop a theory of ontogenetic growth and health in utero and during childhood, unify it with the health deficit model of adult aging, and discuss the transmission of early-life shocks to late-life health deficit accumulation.

Triazole-containing N-acyl homoserine lactones targeting the quorum sensing system in Pseudomonas aeruginosa.

In an attempt to devise new antimicrobial treatments for biofilm infections, the bacterial cell-cell communication system termed quorum sensing has emerged as an attractive target. It has proven possible to intercept the communication system by synthetic non-native ligands and thereby lower the pathogenesis and antibiotic tolerance of a bacterial biofilm. To identify the structural elements important for antagonistic or agonistic activity against the Pseudomonas aeruginosa LasR protein, we report the synthesis and screening of new triazole-containing mimics of natural N-acyl homoserine lactones. A series of azide- and alkyne-containing homoserine lactone building blocks was used to prepare an expanded set of 123 homoserine lactone analogues through a combination of solution- and solid-phase synthesis methods. The resulting compounds were subjected to cell-based quorum sensing screening assays, thereby revealing several bioactive compounds, including 13 compounds with antagonistic activity and 9 compounds with agonistic activity.

Synthesis of oxacyclic scaffolds via dual ruthenium hydride/Brønsted acid-catalyzed isomerization/cyclization of allylic ethers.

A ruthenium hydride/Brønsted acid-catalyzed tandem sequence is reported for the synthesis of 1,3,4,9-tetrahydropyrano[3,4-b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Brønsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa-Pictet-Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.

Ruthenium hydride/Brønsted acid-catalyzed tandem isomerization/N-acyliminium cyclization sequence for the synthesis of tetrahydro-ß-carbolines.

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-ß-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to N-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient "aldehyde-free" alternative to the classical Pictet-Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/N-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively.

Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators.

Many bacterial species are capable of assessing their local population densities through a cell-cell signaling mechanism termed quorum sensing (QS). This intercellular communication process is mediated by small molecule or peptide ligands and their cognate protein receptors. Numerous pathogens use QS to initiate virulence once they achieve a threshold cell number on a host. Consequently, approaches to intercept QS have attracted considerable attention as potential anti-infective therapies. Our interest in the development of small molecule tools to modulate QS pathways motivated us to evaluate triazole-containing analogs of natural N-acyl L-homoserine lactone (AHL) signals as non-native QS agonists and antagonists in Gram-negative bacteria. We synthesized 72 triazole derivatives of five broad structure types in high yields and purities using efficient Cu(I)-catalyzed azide-alkyne couplings. These compounds were evaluated for their ability to activate or inhibit two QS receptors from two prevalent pathogens - LasR from Pseudomonas aeruginosa and AbaR from Acinetobacter baumannii- using bacterial reporter strains. Several triazole derivatives were identified that were capable of strongly modulating the activity of LasR and AbaR. These compounds represent a new and synthetically accessible class of AHL analogs, and could find utility as chemical tools to study QS and its role in bacterial virulence.

Physiological aging and life-cycle labor supply across countries.

We construct a cohort-based frailty index for 180 countries over the period 1990-2019. We use this measure of physiological aging to estimate the impact of deteriorating health on labor force participation. Our three-dimensional panel framework, in which the unit of observation is a cohort in a given country at a given age, allows us to control for a range of unobserved factors. Our identification strategy further exploits a compensating law of physiological aging to account for reverse causality. We find a negative effect of physiological aging on labor market participation: an increase of the frailty index by one percent leads to a reduction of labor force participation of about 0.6 (±0.2) percentage points. Since health deficits (in the frailty index) are accumulated at a rate of about 3 percent per year of life, almost all of the age-related decline in labor force participation can be motivated by deteriorating health.

Physiological aging around the World.

We extract data on physiological aging by computing a frailty index for 201 countries over the period 1990-2019. Using panel estimation techniques, we show that the macro frailty index replicates basic regularities previously observed in related studies of aging at the individual level. We then use the frailty index to highlight trends of global physiological aging and its relationship to economic growth. Holding population age structure fixed, the global frailty index has on average increased by about 2 percent over the last 30 years. The average person has therefore aged by what corresponds to about one life-year of physiological aging. This overall trend is relatively similar across different geographical regions. We also document a negative relationship between physiological aging of the workforce and economic growth. According to our preferred specification, a one percent increase in the frailty index of the workforce is associated with a 1.5 percent decline of GDP per capita. This means that average annual growth of labor productivity would have been 0.1 percentage points higher without physiological aging in the period 1990-2019.

Appropriateness of referrals from primary care for lumbar MRI.

BACKGROUND: International guidelines do not recommend routine imaging, including magnetic resonance imaging (MRI), and seek to guide clinicians only to refer for imaging based on specific indications. Despite this, several studies show an increase in the use of MRI among patients with low back pain (LBP) and an imbalance between appropriate versus inappropriate use of MRI for LBP. This study aimed to investigate to what extent referrals from general practice for lumbar MRI complied with clinical guideline recommendations in a Danish setting, contributing to the understanding and approaches to lumbar MRI for all clinicians managing LBP in the primary sector. MATERIALS AND METHODS: From 2014 to 2018, all referrals for lumbar MRI were included from general practitioners in the Central Denmark Region for diagnostic imaging at a public regional hospital. A modified version of the American College of Radiology Imaging Appropriateness Criteria for LBP was used to classify referrals as appropriate or inappropriate, based on the unstructured text in the GPs' referrals. Appropriate referrals included fractures, cancer, symptoms persisting for more than 6 weeks of non-surgical treatment, previous surgery, candidate for surgery or suspicion of cauda equina. Inappropriate referrals were sub-classified as lacking information about previous non-surgical treatment and duration. RESULTS: Of the 3772 retrieved referrals for MRI of the lumbar spine, 55% were selected and a total of 2051 referrals were categorised. Approximately one quarter (24.5%) were categorised as appropriate, and 75.5% were deemed inappropriate. 51% of the inappropriate referrals lacked information about previous non-surgical treatment, and 49% had no information about the duration of non-surgical treatment. Apart from minor yearly fluctuations, there was no change in the distribution of appropriate and inappropriate MRI referrals from 2014 to 2018. CONCLUSION: The majority of lumbar MRI referrals (75.5%) from general practitioners for lumbar MRI did not fulfil the ACR Imaging Appropriateness Criteria for LBP based on the unstructured text of their referrals. There is a need for referrers to include all guideline-relevant information in referrals for imaging. More research is needed to determine whether this is due to patients not fulfilling guideline recommendations or simply the content of the referrals.

Measurement of body composition: Agreement between methods of measurement by bioimpedance and computed tomography in patients with non-small cell lung cancer.

BACKGROUND AND AIMS: Cancer cachexia is a muscle wasting syndrome which is promoted by the presence of inflammation and metabolic changes. Cancer cachexia has shown predictable for survival, progression of physical impairment as well as patient-reported outcomes. Being able to identify these patients with a clinically applicable method for measuring body composition could lead to early nutritional intervention, possibly preventing progression of cancer cachexia. This study aimed to investigate the agreement between body composition recorded with bioelectrical impedance analysis (BIA) and software analysis of CT scans of patients suffering from cancer with a special emphasis on muscle mass. METHODS: This is a cross-sectional study of newly diagnosed patients with non-small cell lung cancer. All patients had muscle mass (MM) and fat mass (FM) measured by BIA with Tanita Segmental Body Composition Analyzer (BC-418) and by software analysis of CT scans at L3-level with VikingSlice. Secondary parameters (systemic inflammation, physical performance and electrolyte balance) were investigated for possible pitfalls of BIA. Patients who fulfilled best standard practice for BIA measurements, including 4 h of fasting, absence of oedema and no metallic implants, participated in a subgroup analysis. Agreement between method of measurements is investigated with the Bland and Altman method and pitfalls with paired t-test. A satisfactory agreement of BIA and CT measurements is established as ±10%. RESULTS: A total of 60 patients participated in the study amongst which 37 participated in the subgroup analysis. The bias between methods of measurement for MM was 4.74 ± 11.55% (P = 0.002) with limits of agreement (LoA) of -17.91 to 27.38%. In the subgroup analysis, the bias of MM was 3.06 ± 10.71% (P = 0.091) and LoA were -17.94 to 24.06%. In the analysis of secondary parameters, significant differences between methods were found in patients with normal hand grip strength (1.83 kg, P = 0.023) and those performing under gender and age-specific cut-offs in the 30-s sit to stand test (5.15 kg, P = 0.009). CONCLUSIONS: BIA and CT image analysis were not comparable for body composition measurements. BIA overestimated MM and underestimated FM with LoA outside that of the clinically assessed acceptable difference. Bias was reduced and LoA narrowed in the subgroup analysis however not to acceptable levels. This study finds it possible that patients with low physical performance are liable to larger overestimations of MM with BIA than those with normal physical performance.

Categorisation of lumbar spine MRI referrals in Denmark as compliant or non-compliant to international imaging guidelines: an inter-rater reliability study.

BACKGROUND: Managing low back pain (LBP) often involves MRI despite the fact that international guidelines do not recommend routine imaging. To allow us to explore the topic and use this knowledge in further research, a reliable method to review the MRI referrals is needed. Consequently, this study aimed to assess the inter-rater reliability of a method evaluating lumbar spine MRI referrals' appropriateness. METHODS: Four inexperienced students (chiropractic master's students) and a senior clinician (chiropractor) were included as independent raters in this inter-rater reliability study. Lumbar spine MRI referrals from primary care on patients (> 18 years) with LBP with or without leg pain were included. The referrals were classified using a modified version of the American College of Radiology (ACR) imaging appropriateness criteria for LBP. Categories of appropriate referrals included; fractures, cancer, previous surgery, candidate for surgery or suspicion of cauda equina. Inappropriate referrals included lacking information on previous non-surgical treatment, no word on non-surgical treatment duration, or "other reasons" for inappropriate referrals. After two rounds of training and consensus sessions, 50 lumbar spine MRI referrals were reviewed independently by the five raters. Inter-rater reliability was quantified using unweighted Kappa statistics, and the observed agreement was calculated with both a pairwise comparison and an overall five-rater comparison. RESULTS: Inter-rater reliability was substantial, with a Kappa value for appropriate vs. inappropriate referrals of 0.76 (95% CI: 0.55-0.89). When six and eight subcategories were evaluated, the Kappa values were 0.77 (95% CI: 0.58-0.91) and 0.82 (95% CI: 0.72-0.92), respectively. The overall percentage of agreement for appropriate and inappropriate referrals was 92% and ranged from 88 to 98% for the pairwise comparisons of the five raters' results. For the six and eight subcategories, the overall agreement was 92 and 88%, respectively, ranging from 88 to 98% and 84-92%, respectively, for the pairwise comparisons. CONCLUSION: The inter-rater reliability of the evaluation of the appropriateness of lumbar spine MRI referrals, according to the modified ACR-appropriateness criteria, was found to range from substantial to almost perfect and can be used for research and quality assurance purposes.

Developing and validating COVID-19 adverse outcome risk prediction models from a bi-national European cohort of 5594 patients.

Patients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that machine learning (ML) models could be used to predict risks at different stages of management and thereby provide insights into drivers and prognostic markers of disease progression and death. From a cohort of approx. 2.6 million citizens in Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. SARS-CoV-2 positive cases from the United Kingdom Biobank was used for external validation. The ML models predicted the risk of death (Receiver Operation Characteristics-Area Under the Curve, ROC-AUC) of 0.906 at diagnosis, 0.818, at hospital admission and 0.721 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. Common risk factors, included age, body mass index and hypertension, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission. ML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. We provide access to an online risk calculator based on these findings.

Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet-Spengler-Type Reactions.

A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles (THCAs) has been developed. The strategy relies on two types of 6-exo-trig cyclization of 3-substituted indole substrates. Enantioselective domino Friedel-Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid derivatives (with up to >99% ee), and the first examples of exocyclic Pictet-Spengler reactions to form THCAs are reported.

Motion correction in simultaneous PET/MR brain imaging using sparsely sampled MR navigators: a clinically feasible tool.

BACKGROUND: We present a study performing motion correction (MC) of PET using MR navigators sampled between other protocolled MR sequences during simultaneous PET/MR brain scanning with the purpose of evaluating its clinical feasibility and the potential improvement of image quality. FINDINGS: Twenty-nine human subjects had a 30-min [(11)C]-PiB PET scan with simultaneous MR including 3D navigators sampled at six time points, which were used to correct the PET image for rigid head motion. Five subjects with motion greater than 4 mm were reconstructed into six frames (one for each navigator) which were averaged to one image after MC. The average maximum motion magnitude observed was 3.9 ± 2.4 mm (1 to 11 mm). Visual evaluation by a nuclear medicine physician of the five subjects' motion corrected rated three of the five images blurred before motion correction, while no images were rated blurred after. The image quality was scored on a scale of 1-5, 5 being best. The score changed from an average of 3.4 before motion correction to 4.0 after. There was no correlation between maximum motion magnitude and rating. Quantitative SUVr scoring did not change markedly with motion correction. CONCLUSIONS: Sparsely sampled navigators can be used for characterization and correction of head motion. A slight, overall decrease in blurring and an increase in image quality with MC was found, but without impact on clinical interpretation. In future studies with noteworthy motion artifacts, our method is an important and simple-to-use tool to have available for motion correction.

Life expectancy and human capital: evidence from the international epidemiological transition.

Exploiting preintervention variation in mortality from various infectious diseases, together with the time variation arising from medical breakthroughs in the late 1940s and the 1950s, this study examines how a large positive shock to life expectancy influenced the formation of human capital within countries during the second half of the 20th century. The results establish that the rise in life expectancy was behind a significant part of the increase in human capital over this period. According to the baseline estimate, for one additional year of life expectancy, years of schooling increase by 0.17 year. Moreover, the evidence suggests that declines in pneumonia mortality are the underlying cause of this finding, indicating that improved childhood health increases human capital investments.

Synthesis of tetrahydro-ß-carbolines via isomerization of N-allyltryptamines: a metal-catalyzed variation on the Pictet-Spengler theme.

An efficient and broadly applicable alternative to the classical Pictet-Spengler synthesis of tetrahydro-ß-carbolines is presented. The method relies on metal-catalyzed isomerization of allylic amines to form reactive iminium intermediates which can be trapped by a tethered indole nucleophile.