Space research to explore novel biochemical insights on Earth.

Travel to space has overcome unprecedent technological challenges and this has resulted in transfer of these technological results on Earth to better our lives. Health technology, medical devices, and research advancements in human biology are the first beneficiaries of this transfer. The real breakthrough came with the International Space Station, which endorsed multidisciplinary international scientific collaborations and boosted the research on pathophysiological adaptation of astronauts to life on space. These studies evidenced that life in space appeared to have exposed the astronauts to an accelerated aging-related pathophysiological dysregulation across multiple systems. In this review we emphasize the interaction between several biomarkers and their alteration in concentrations/expression/function by space stress factors. These altered interactions, suggest that different biochemical and hormonal factors, and cell signals, contribute to a complex network of pathophysiological mechanisms, orchestrating the homeostatic dysregulation of various organs/metabolic pathways. The main effects of space travel on altering cell organelles biology, ultrastructure, and cross-talk, have been observed in cell aging as well as in the disruption of metabolic pathways, which are also the causal factor of rare inherited metabolic disorders, one of the major pediatric health issue. The pathophysiologic breakthrough from space research could allow the development of precision health both on Earth and Space by promoting the validation of improved biomarker-based risk scores and the exploration of new pathophysiologic hypotheses and therapeutic targets. Nonstandard abbreviations: International Space Station (ISS), Artificial Intelligence (AI), European Space Agency (ESA), National Aeronautics and Space Agency (NASA), Low Earth Orbit (LEO), high sensitive troponin (hs-cTn), high sensitive troponin I (hs-cTn I), high sensitive troponin T, Brain Natriuretic Peptide (BNP), N terminal Brain Natriuretic Peptide (NT-BNP), cardiovascular disease (CVD), parathyroid hormone (PTH), urinary hydroxyproline (uHP), urinary C- and N-terminal telopeptides (uCTX and uNTX), pyridinoline (PYD), deoxypyridinoline (DPD), half-time (HF), serum Bone Alkaline Phosphatase (sBSAP), serum Alkaline Phosphatase (sAP), Carboxy-terminal Propeptide of Type 1 Procollagen (P1CP), serum Osteocalcin (sOC)), advanced glycation end products (AGEs), glycated hemoglobin A1c (HbA1c), Insulin-like growth factor 1 (IGF1), Growth Hormone (GH), amino acid (AA), ß-hydroxy-ß methyl butyrate (HMB), maple syrup urine disease (MSUD), non-communicable diseases (NCDs).

A real-time biphasic Kalman filter-based model for estimating human core temperature from heart rate measurements for application in the occupational field.

Introduction: Early identification of hypothermia or hyperthermia is of vital importance, and real-time monitoring of core temperature (CT) of the workers exposed to thermal environments is an extremely valuable tool. From the existing literature studies, the model developed by Buller et al. in their study of 2013 that generates real-time estimates of CT from heart rate (HR) measurements using the Kalman filter (KF) shows good potential for occupational application. However, some aspects could be improved to reliably handle the existing very wide range of workers and work activities. This study presents a real-time CT estimation model, called the Biphasic Kalman filter-based (BKFB) model, based on HR measurement, with characteristics suited to application in the occupational field. Methods: Thirteen healthy subjects (six female and seven male) were included in the study to perform three consecutive tasks simulating work activities. During each test, an ingestible CT sensor was used to measure CT and a HR sensor to measure HR. The KF methodology was used to develop the BKFB model. Results: An algorithm with a biphasic structure was developed using two different models for the increasing and decreasing phases of CT, with the ability to switch between the two based on an HR threshold. CT estimates were compared with CT measurements, and with respect to overall root mean square error (RMSE), the BKFB model achieved a sizeable reduction (0.28 ± 0.12°C) compared to the Buller et al. model (0.34 ± 0.16°C). Discussion: The BKFB model introduced some modifications over the Buller et al. model for a more effective application in the occupational field. It was developed using data collected from a sample of workers (heavily weighted toward middle-aged, not very fit, and with a considerable fraction of female workers), and it also included two different modeling of CT (for the up- and down-phases), which allowed for better behavioral modeling in the two different stages. The BKFB model provides CT estimates reasonably in comparison to the measured intra-abdominal temperature values in both the activity and recovery phases but is more practical and easier to use for a real-time monitoring system of the workers' thermal states.

High-Sensitivity Cardiac Troponin and the Management of Congenital Heart Disease in Newborns and Infants.

BACKGROUND: Early cardiac interventions in newborns and infants suspected for congenital heart disease (CHD) decrease morbidity and mortality. After updating current evidence on the use of cardiac troponins (cTn) in the context of CHD for risk stratification at early ages, we discuss relevant issues, starting from the evidence that only the measurement of the cTnT form is useful in this population. CONTENT: In newborns/infants with CHD, the cTnT concentration increase is correlated with: (a) cardiac stress and hemodynamic parameters, but not with the type of CHD; (b) volume overload/right ventricular pressure overload; (c) postoperative hypoperfusion injury and mortality; and (d) effects of cardioprotective strategies. For infants with CHD, high-sensitivity cTnT (hs-cTnT) concentrations >25 ng/L are an independent predictor of poor outcomes. Transitioning from cTnT to hs-cTnT in newborns/infants improves the identification of: (a) physiopathological mechanisms and factors that increased hs-cTnT early after birth; (b) myocardial injury, even when subclinical; (c) identification of patients requiring immediate therapeutic interventions; and (d) 99th percentile upper reference limits (URLs). However, no reliable URLs are currently available to allow the detection of myocardial injury associated with CHD in newborns/infants. SUMMARY: Additional data evaluating the clinical value of hs-cTnT in the risk stratification of newborns/infants with CHD who may suffer myocardial injury is needed. Validating the measurement, possibly in amniotic fluid samples, and improving the interpretation of hs-cTnT concentrations in the prenatal period, at birth and within 1 year of age are crucial to change CHD mortality/morbidity trends in the pediatric population.

Foreign body ingestion in children: Definition of a nomogram to predict surgical or endoscopic intervention.

BACKGROUND AND AIMS: Foreign body ingestion (FBI) in children requires early identification to prevent adverse outcomes and may necessitate endoscopic or surgical intervention. This study aims to develop a nomogram that identifies children who require urgent surgical or endoscopic intervention by using the patient's medical history and clinical parameters collected at admission. METHODS: This study is a retrospective review (01/2015-12/2020) of a multicenter case series of children admitted for FBI. Data from 5864 records from 24 hospitals in Italy were analyzed. Logistic regression models were used to establish the probability of requiring surgical or endoscopic intervention based on patient history and clinical characteristics. The nomogram representing the results from the multivariable model was reported to examine the propensity for surgery/endoscopy. RESULTS: The study identified a significant association between intervention and various factors, including type of foreign body (blunt: reference category, disk battery (odds ratio OR:4.89), food bolus (OR:1.88), magnets (OR:2.61), sharp-pointed (OR:1.65), unknown (OR:1.02)), pre-existing diseases or conditions (OR 3.42), drooling (OR 10.91), dysphagia (OR 5.58), vomiting (OR 3.30), retrosternal pain (OR 5.59), abdominal pain (OR 1.58), hematemesis (OR 2.82), food refusal/poor feeding (OR 2.99), and unexplained crying (OR 2.01). The multivariable regression model showed good calibration and discrimination ability, with an area under the ROC curve of 0.77. CONCLUSIONS: This study developed the first nomogram to predict the probability of the need for surgical or endoscopic intervention in children with FBI, based on the information collected at admission. The nomogram will aid clinicians in identifying children who require early intervention to prevent adverse outcomes.

Prediction of atherosclerotic cardiovascular risk in early childhood.

Atherosclerotic lesions are present even in very young individuals and therefore, risk stratification for cardiovascular (CV) disease should be implemented in childhood to promote early prevention strategies. In this review we critically appraise clinical, biochemical and genetic biomarkers available for pediatric clinical practice, which might be integrated to build effective algorithms to identify children at risk of future CV events. The first critical issue is to characterize in children aged 2-5 years, those CV risk factors/clinical conditions associated with dramatically accelerated atherosclerosis. Presence of clinical conditions such as obesity, diabetes mellitus, Kawasaki disease, etc., or positive family history for premature CV disease should be evaluated. Subsequently, a complete lipid profile and Lipoprotein(a) determination are recommended for children with increased baseline CV risk. Individuals with altered lipid profile could then undergo genetic testing for monogenic dyslipidemias to identify children with high CV genetic risk, who will be directed to appropriate therapeutic options. In perspective, calculation of a polygenic risk score, based on the analysis of several common single-nucleotide polymorphisms, could be integrated for better risk assessment. We here emphasize the importance of a "holistic" strategy integrating biochemical, anamnestic and genetic data to stratify CV risk in early childhood.

Mitigating heat effects in the workplace with a ventilation jacket: Simulations of the whole-body and local human thermophysiological response with a sweating thermal manikin in a warm-dry environment.

Climate change is increasingly affecting human well-being and will inevitably impact on occupational sectors in terms of costs, productivity, workers' health and injuries. Among the cooling garment developed to reduce heat strain, the ventilation jacket could be considered for possible use in workplaces, as it is wearable without limiting the user's mobility and autonomy. In this study, simulations with a sweating manikin are carried out to investigate the effects of a short-sleeved ventilation jacket on human thermophysiological responses in a warm-dry scenario. Simulations were performed in a climatic chamber (air temperature = 30.1 °C; air velocity = 0.29 m/s; relative humidity = 30.0 %), considering two constant levels of metabolic rate M (M1 = 2.4 MET; M2 = 3.2 MET), a sequence of these two (Work), and three levels of fan velocities (lf = 0; lf=2; lf=4). The results revealed a more evident impact on the mean skin temperature (Tsk) compared to the rectal temperature (Tre), with significant decreases (compared to fan-off) at all M levels, for Tsk from the beginning and for Tre from the 61st minute. Skin temperatures of the torso zones decreased significantly (compared to fan-off) at all M levels, and a greater drop was registered for the Back. The fans at the highest level (lf=4) were significantly effective in improving whole-body and local thermal sensations when compared to fan-off, at all M levels. At the intermediate level (lf=2), the statistical significance varied with thermal zone, M and time interval considered. The results of the simulations also showed that the Lower Torso needs to be monitored at M2 level, as the drop in skin temperature could lead to local overcooling and thermal discomfort. Simulations showed the potential effectiveness of the ventilation jacket, but human trials are needed to verify its cooling power in real working conditions.

Does a Soft Actuated Back Exosuit Influence Multimodal Physiological Measurements and User Perception During an Industry Inspired Task?

Back support soft exosuits are promising solutions to reduce risk of musculoskeletal injuries at workplaces resulting from physically demanding and repetitive lifting tasks. Design of novel active exosuits address the impact on the muscle activity and metabolic costs but do not consider other critical aspects such as comfort and user perception during the intended tasks. Thus, in this study, we describe a novel soft active exosuit in line with its impact on physiological and subjective measures during lifting. We tested four healthy participants who performed repetitive lifting tasks with and without this exosuit. The exosuit provided assistance proportional to the lumbar flexion angle measured using an inertial measurement unit. We measured the participant's multimodal physiological measures including surface electromyography, metabolic cost, heart rate, and skin temperature. We also measured subjective scores on user exertion, task load, and device acceptability. All participants perceived a reduction in task load when using the exosuit. Three participants showed reduction of muscle activity for the erector spinae muscles. The metabolic costs and heart rate reserve reduced for two participants, with similar trends for skin temperature. For future development of workplace exosuits, we recommend incorporating assessments of both physiological and subjective measures, considering the user-dependent response to the exosuit.

Striving for a pragmatic contribution of biomarkers results to lifelong health care.

BACKGROUND: The increased role of preventive medicine in healthcare and the rapid technological advancements, have deeply changed the landscape of laboratory medicine. In particular, increased investments in newborn screening tests and policies have been observed. Aim of this paper is to characterize how laboratory professionals engaged in clinical chemistry or newborn screening, in collaboration with experts in econometric, bioinformatics, and biostatistics may address a pragmatic use of laboratory results in the decision-making process oriented toward improvement of health care outcomes. CONTENT: The effectiveness of biomarkers on healthcare depends on several factors such as analytical performance, prevalence of the disease, integration of the test within the diagnostic algorithm, associated costs, and social/economic impact of false positive and false negative results. Cost-effectiveness analysis needs to be performed and reliability achieved, by overcoming analytical pitfalls and by improving interpretative criteria. These are challenging issues common to clinical chemistry and newborn screening tests. Following the experience in clinical chemistry, one of the main issues to be approached in newborn screening tests, is the lack of harmonization of results obtained by different methods and the limited healthcare effectiveness. SUMMARY: The focus on prevention is a crucial opportunity for laboratory medicine to change how to approach the effectiveness of biomarkers on healthcare. The consolidation within clinical laboratories of professionals with different technical and methodological expertise coupled with the need to produce and manage large sets of data, require the cooperation of professionals from other disciplines to characterize the impact of the tests on epidemiological outcomes for health care policy making process.

How the EU Cohesion Policy targeted at R&D and innovation impacts the productivity, employment and exports of SMEs in Estonia.

The aim of this empirical investigation is to assess how the support targeted at R&D and innovation in the European Union Cohesion Policy Programme 2014-2020 affects the labour productivity, employment and exports of small and medium-sized companies. We estimate the treatment effects of two R&D financial support activities using a semiparametric efficient estimator with over-identified moment conditions and inverse probability weighting. The impact assessment uses population data on small and medium-sized enterprises in Estonia, the European Union member state that benefits most per capita from Cohesion Fund allocations. We found that support for R&D and innovation from the Cohesion Policy had a positive short-term effect on labour productivity and employment over the estimation period 2014-2018, and that the size and robustness of the effect were strongest for labour productivity. The short-term effect on exporting was ambiguous.

Reference intervals for thyroid biomarkers to enhance the assessment of thyroid status in childhood and adolescence.

OBJECTIVES: The determination of assay-dependent upper and lower reference limits (URL, LRL) of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) during childhood and adolescence, is challenging. METHODS: Thyroid hormones were measured via the Abbott Alinity system in 502 euthyroid children partitioned in the following age groups: ≤2, 2.1-10, and 10.1-18 years. The 97.5th and 2.5th percentiles (URL and LRL) were derived according to CLSI EP28- A3c guidelines. Quantile regression models were used to assess: (a) 90% confidence intervals of the URL and LRL, (b) the effect of age on URL and LRL within each age class and on overall age range, (c) the difference between the URLs and LRLs estimated for each age partition with an estimate of the confidence interval divided by the reference interval being derived (CI/RI). RESULTS: The CI/RI for the LRLs are smaller as compared to the URLs, except for FT4 for the 2.1-10 years age group. Considering the CI/RI and the overlap between CIs across the three age groups, one single LRL might be considered for TSH, FT3 and FT4 between 0 and 18 years. However, for the URL, there was a noticeable decrease in the URL over the 3 age groups for all three biomarkers, with there being no overlap in CIs for the URL between the ≤2 vs. the 10.1-19 years age groups. CONCLUSIONS: A common LRL for TSH, FT4 and FT3 for patients aged ≤18 years may be utilized when these biomarkers are measured with the Alinity system. For the URLs the use of age-specific URLs for these biomarkers is recommended.

Individual risk prediction of high grade prostate cancer based on the combination between total prostate-specific antigen (PSA) and free to total PSA ratio.

OBJECTIVES: Clinical practice guidelines endorse the stratification of prostate cancer (PCa) risk according to individual total prostate-specific antigen (tPSA) values and age to enhance the individual risk-benefit ratio. We defined two nomograms to predict the individual risk of high and low grade PCa by combining the assay of tPSA and %free/tPSA (%f/tPSA) in patients with a pre-biopsy tPSA between 2 and 10 µg/L. METHODS: The study cohort consisted of 662 patients that had fPSA, tPSA, and a biopsy performed (41.3% with a final diagnosis of PCa). Logistic regression including age, tPSA and %f/tPSA was used to model the probability of having high or low grade cancer by defining 3 outcome levels: no PCa, low grade (International Society of Urological Pathology grade, ISUP<3) and high grade PCa (ISUP≥3). RESULTS: The nomogram identifying patients with: (a) high vs. those with low grade PCa and without the disease showed a good discriminating capability (∼80%), but the calibration showed a risk of underestimation for predictive probabilities >30% (a considerable critical threshold of risk), (b) ISUP<3 vs. those without the disease showed a discriminating capability of 63% and overestimates predictive probabilities >50%. In ISUP 5 a possible loss of PSA immunoreactivity has been observed. CONCLUSIONS: The estimated risk of high or low grade PCa by the nomograms may be of aid in the decision-making process, in particular in the case of critical comorbidities and when the digital rectal examinations are inconclusive. The improved characterization of the risk of ISUP≥3 might enhance the use for magnetic resonance imaging in this setting.

Managing the impact of inter-method bias of prostate specific antigen assays on biopsy referral: the key to move towards precision health in prostate cancer management.

OBJECTIVES: We assessed the inter-method bias of total (tPSA) and free (fPSA) prostate-specific antigen (PSA) immunoassays to establish if tPSA-based risk thresholds for advanced prostate cancer (PCa), obtained from one method (Roche) can be converted into the corresponding concentrations assayed by other methods. Then we evaluated the impact of the bias of tPSA and fPSA on the estimation of the %f/tPSA ratio and performed a re-calibration of the proposed thresholds for the %f/tPSA ratio according to the assay used. METHODS: tPSA and fPSA were measured in 135 and 137 serum samples, respectively by Abbott Alinity i, Beckman Access Dxl, Roche Cobas e801, and Siemens Atellica IM analytical platforms. Scatterplots, Bland-Altman diagrams, Passing-Bablok (PB) were used to inspect and estimate the systematic and proportional bias between the methods. The linear equations with confidence intervals of the parameter estimates were used to transform the tPSA risk thresholds for advanced PCa into the corresponding concentrations measurable by the other analytical methods. To construct a correction coefficient for converting the %f/tPSA ratio from one method to the other, PB and non-parametric boostrapping were used. RESULTS: The inter-method bias is not constant but strictly linear allowing the conversion of PSA results obtained from Roche into the other assays, which underestimate tPSA vs. Roche. Siemens and Abbott vs. Roche and Beckman assays, being characterized by a positive and a negative proportional bias for tPSA and fPSA measurements, tend to overestimate the %f/tPSA ratio. CONCLUSIONS: There is a consistent risk to miss advanced PCa, if appropriate conversion factors are not applied.

Thyroid Function and Metabolic Syndrome in Children and Adolescents with Neuromotor Disability.

Thyroid function plays a crucial role in nervous system integrity and metabolic homeostasis. We evaluated the pattern of TSH, FT4 and FT3 release in children with neuromotor impairment (NI) in relationship with metabolic syndrome (MS). We enrolled 55 patients with NI and 30 controls. Clinical parameters, thyroid function and MS presence were recorded. Principal component analysis (PCA), cluster analysis, and logistic regression models were performed. MS was detected in 54.5% of patients. Four clusters were identified: the first one included only controls and, contrasting with cluster 4, was exclusively characterized by children with disability and MS. This latter showed increased FT4 and FT3 and decreased TSH levels. Cluster 2, characterized by disability without MS showed high FT4 and FT3, whereas cluster 3 with low FT4 and FT3 mainly included disability (90%) and showed prevalent MS (57%). The association between TSH and NI is represented by a U-shape structure. The TSH, FT3 and FT4 release patterns may reflect thyrotropic adaptation, allostatic response and compensatory mechanisms. These mechanisms, found in both MS and disability, show that the odds of having a condition of NI with or without MS increase as the TSH values deviate, in both directions, from a value of 2.5 mLU/mL.

Fibroblast growth factor 23: translating analytical improvement into clinical effectiveness for tertiary prevention in chronic kidney disease.

OBJECTIVES: Fibroblast growth factor 23 (FGF23) plays a key role in the pathophysiology of chronic kidney disease (CKD) and of the associated cardiovascular diseases, ranking on the crossroads of several evolving areas with a relevant impact on the health-care system (ageing, treatment of CKD and prevention from cardiovascular and renal events). In this review, we will critically appraise the overall issues concerning the clinical usefulness of FGF23 determination in CKD, focusing on the analytical performances of the methods, aiming to assess whether and how the clinical introduction of FGF23 may promote cost-effective health care policies in these patients. CONTENT: Our comprehensive critical appraisal of the literature revealed that we are currently unable to establish the clinical usefulness of FGF23 measured by ELISA in CKD, as stability issues and suboptimal analytical performances are the major responsible for the release of misleading results. The meta-analytical approach has failed to report unambiguous evidence in face of the wide heterogeneity of the results from single studies. SUMMARY AND OUTLOOK: Our review has largely demonstrated that the clinical usefulness depends on a thorough analytical validation of the assay. The recent introduction of chemiluminescent intact-FGF23 (iFGF23) assays licensed for clinical use, after passing a robust analytical validation, has allowed the actual assessment of preliminary risk thresholds for cardiovascular and renal events and is promising to capture the iFGF23 clinically relevant changes as a result of a therapeutic modulation. In this perspective, the analytical optimization of FGF23 determination may allow a marriage between physiology and epidemiology and a merging towards clinical outcomes.

A potential wearable solution for preventing heat strain in workplaces: The cooling effect and the total evaporative resistance of a ventilation jacket.

The increase in average seasonal temperatures has an impact in the occupational field, especially for those sectors whose work activities are performed outdoors (agricultural, road and construction sectors). Among the adaptation measures and solutions developed to counteract occupational heat strain, personal cooling garments represent a wearable technology designed to remove heat from the human body, enhancing human performance. This study aims to investigate the effectiveness and the cooling power of a specific cooling garment, i.e. a ventilation jacket, by quantifying the evaporative heat losses and the total evaporative resistance both when worn alone and in combination with a work ensemble, at three adjustments of air ventilation speed. Standardised "wet" tests in a climatic chamber were performed on a sweating manikin in isothermal conditions considering three clothing ensembles (single jacket, work ensemble and a combination of both) and three adjustments of fan velocity. Results showed a significant increase (p < 0.001) in evaporative heat loss values when the fan velocity increased, particularly within the trunk zones for all the considered clothing ensembles, showing that fans enhanced the dissipation by evaporation. The cooling power, quantified in terms of percent changes of evaporative heat loss, showed values exceeding 100% when fans were on, in respect to the condition of fans-off, for the trunk zones except for the Chest. A significant (p < 0.01) decrease (up to 42.3%) in the total evaporative resistance values of the jacket, coupled with the work ensemble, was found compared to the fans-off condition. Results confirmed and quantified the cooling effect of the ventilation jacket which enhanced the evaporative heat losses of the trunk zones, helping the body to dissipate heat and showing the potential for a heat adaptation measure to be developed.

A Multivariate Analysis of "Metabolic Phenotype" Patterns in Children and Adolescents with Obesity for the Early Stratification of Patients at Risk of Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MS) is closely linked to obesity; however, not all individuals with obesity will develop obesity-related complications and a metabolically healthy obesity (MHO) group is also described. OBJECTIVE: To perform a multivariate analysis (MVA) of the anthropometric and biochemical data in pediatric patients with obesity to reveal a "phenotype" predictive for MS. METHODS: We analyzed 528 children with obesity (OB) and 119 normal-weight pediatric patients (NW). Adiposity indices were recorded, and MS was detected. MVA was performed. RESULTS: Analysis of the structure of correlation of the variables showed that the variables of waist circumference (WC), body mass index (BMI), and estimated fat mass (eFM) were positively correlated with each other as a whole. In addition, the variables of the triglycerides (TG), triglyceride-glucose (TyG) index, and visceral adiposity index were positively correlated with each other as a whole, although none were correlated with the variables of BMI z-score, waist-to-height ratio, WC, eFM, or weight. The variables that related to insulin resistance (IR) and dyslipidemia were crucial for the early stratification of patients at risk of MS. CONCLUSIONS: Independently of body weight, IR, dyslipidemia, hypertriglyceridemia, and fat distribution seem to be the strongest MS risk factors. The early detection of and intervention in these modifiable risk factors are useful to protect children's health.