Identification of diagnostic biomarkers used in the diagnosis of cardiovascular diseases and diabetes mellitus: A systematic review of quantitative studies.

AIMS: To perform a systematic review of studies that sought to identify diagnostic biomarkers for the diagnosis of cardiovascular diseases (CVDs) and diabetes mellitus (DM), which could be used in low- and middle-income countries (LMICs) where there is a lack of diagnostic equipment, treatments and training. MATERIALS AND METHODS: Papers were sourced from six databases: the British Nursing Index, Google Scholar, PubMed, Sage, Science Direct and Scopus. Articles published between January 2002 and January 2023 were systematically reviewed by three reviewers and appropriate search terms and inclusion/exclusion criteria were applied. RESULTS: A total of 18 studies were yielded, as well as 234 diagnostic biomarkers (74 for CVD and 160 for DM). Primary biomarkers for the diagnosis of CVDs included growth differentiation factor 15 and neurogenic locus notch homologue protein 1 (Notch1). For the diagnosis of DM, alpha-2-macroglobulin, C-peptides, isoleucine, glucose, tyrosine, linoleic acid and valine were frequently reported across the included studies. Advanced analytical techniques, such as liquid chromatography mass spectrometry, enzyme-linked immunosorbent assays and vibrational spectroscopy, were also repeatedly reported in the included studies and were utilized in combination with traditional and alternative matrices such as fingernails, hair and saliva. CONCLUSIONS: While advanced analytical techniques are expensive, laboratories in LMICs should carry out a cost-benefit analysis of their use. Alternatively, laboratories may want to explore emerging techniques such as infrared, Fourier transform-infrared and near-infrared spectroscopy, which allow sensitive noninvasive analysis.

Authentication of Covid-19 Vaccines Using Synchronous Fluorescence Spectroscopy.

The present study demonstrates the potential of synchronous fluorescence spectroscopy and multivariate data analysis for authentication of COVID-19 vaccines from various manufacturers. Synchronous scanning fluorescence spectra were recorded for DNA-based and mRNA-based vaccines obtained through the NHS Central Liverpool Primary Care Network. Fluorescence spectra of DNA and DNA-based vaccines as well as RNA and RNA-based vaccines were identical to one another. The application of principal component analysis (PCA), PCA-Gaussian Mixture Models (PCA-GMM)) and Self-Organising Maps (SOM) methods to the fluorescence spectra of vaccines is discussed. The PCA is applied to extract the characteristic variables of fluorescence spectra by analysing the major attributes. The results indicated that the first three principal components (PCs) can account for 99.5% of the total variance in the data. The PC scores plot showed two distinct clusters corresponding to the DNA-based vaccines and mRNA-based vaccines respectively. PCA-GMM clustering complemented the PCA clusters by further classifying the mRNA-based vaccines and the GMM clusters revealed three mRNA-based vaccines that were not clustered with the other vaccines. SOM complemented both PCA and PCA-GMM and proved effective with multivariate data without the need for dimensions reduction. The findings showed that fluorescence spectroscopy combined with machine learning algorithms (PCA, PCA-GMM and SOM) is a useful technique for vaccination verification and has the benefits of simplicity, speed and reliability.

A click mediated route to a novel fluorescent pyridino-extended calix[4]pyrrole sensor: synthesis and binding studies.

A novel fluorescent aryl-extended phenoxycalix[4]pyrrole ditopic sensor with enhanced cation recognition properties was efficiently synthesized via click chemistry and characterized through both molecular fluorescence and nuclear magnetic resonance spectroscopy. Results demonstrate the selectivity of this fluorescent sensor for fluoride when taking into account its interaction with anions, while its cation binding properties showed selectivity for iron, and its sensing properties for several cations in dimethylsulfoxide. This work introduces a new ditopic receptor able to complex major environmentally relevant species and depicts the importance of click chemistry in the introduction of new tetra-chromophoric calix[4]pyrrole binding platforms with specific photophysical properties.

Evaluation of portable near-infrared spectroscopy for authentication of mRNA based COVID-19 vaccines.

Since its identification in 2019, Covid-19 has spread to become a global pandemic. Until now, vaccination in its different forms proves to be the most effective measure to control the outbreak and lower the burden of the disease on healthcare systems. This arena has become a prime target to criminal networks that spread counterfeit Covid-19 vaccines across the supply chain mainly for profit. Counterfeit vaccines provide false sense of security to individuals, heightens the risk of exposure and outbreak of the virus, and increase the risk of harm linked to Covid-19 infection. Moreover, the increase in counterfeit vaccines feeds hesitancy towards vaccination and erodes the trust in mass immunisation programmes. It is therefore of paramount importance to work on rapid and reliable methods for vaccine authentication. Subsequently this work utilised a portable and non-destructive near infrared (NIR) spectroscopic method for authentication of Covid-19 vaccines. A total of 405 Covid-19 vaccines samples, alongside their main constituents, were measured as received through glass vials. Spectral quality and bands were inspected by considering the raw spectra of the vaccines. Authentication was explored by applying principal component analysis (PCA) to the multiplicative scatter correction-first derivative spectra. The results showed that NIR spectra of the vaccine featured mainly bands corresponding to the mRNA active ingredient. Fewer bands corresponded to the excipients and protein spectra. The vaccines NIR spectra were strongly absorbing with maximum absorbances up to 2.7 absorbance units and that differentiated them from samples containing normal saline only (constituent reported for counterfeit Covid-19 vaccines). Clustering based on PCA offered optimal authentication of Covid-19 vaccines when applied over the range of 9000-4000 cm-1These findings shed light on the potential of using NIR for analysing Covid-19 vaccines and presents a rapid and effective initial technique for Covid-19 vaccine authentication.

WtsWrng Interim Comparative Effectiveness Evaluation and Description of the Challenges to Develop, Assess, and Introduce This Novel Digital Application in a Traditional Health System.

Science and technology have evolved quickly during the two decades of the 21st century, but healthcare systems are grounded in last century's structure and processes. Changes in the way health care is provided are demanded; digital transformation is a key driver making healthcare systems more accessible, agile, efficient, and citizen-centered. Nevertheless, the way healthcare systems function challenges the development (Innovation + Development and regulatory requirements), assessment (methodological guidance weaknesses), and adoption of digital applications (DAs). WtsWrng (WW), an innovative DA which uses images to interact with citizens for symptom triage and monitoring, is used as an example to show the challenges faced in its development and clinical validation and how these are being overcome. To prove WW's value from inception, novel approaches for evidence generation that allows for an agile and patient-centered development have been applied. Early scientific advice from NICE (UK) was sought for study design, an iterative development and interim analysis was performed, and different statistical parameters (Kappa, B statistic) were explored to face development and assessment challenges. WW triage accuracy at cutoff time ranged from 0.62 to 0.94 for the most frequent symptoms attending the Emergency Department (ED), with the observed concordance for the 12 most frequent diagnostics at hospital discharge fluctuating between 0.4 to 0.97; 8 of the diagnostics had a concordance greater than 0.8. This experience should provoke reflective thinking for DA developers, digital health scientists, regulators, health technology assessors, and payers.

Application of Doehlert experimental design for the removal of radium from aqueous solution by cross-linked phenoxycalix[4]pyrrole-polymer using Ba(II) as a model.

Ra-226 is a naturally occurring radionuclide that is derived from uranium-238 series, and it is present at low concentrations in rocks, soil, and groundwater. Many efforts have been exerted for the decontamination of radium from aqueous media in order to meet the increasing water demand of the population. To this aim, a new polymer based on cross-linked phenoxycalix[4]pyrrole was designed and employed in solid/liquid extractions in order to remove radium from aqueous solutions. Preliminary experiments have highlighted the capability of this polymer to extract 22% of Ra-226 from aqueous acidic solution. The optimization of the extraction experimental factors in the direction to attend the maximum removal of Ra-226 from water was carried out employing Ba2+ due to its similar chemical behavior as radium, in order to minimize the consumption of Ra-226 solutions and the risk of radioactive contamination. Doehlert experimental plan was then applied to determine the optimal conditions (pH, time, temperature) for the removal of Ba2+ from aqueous solutions.

Optimal design of clinical trials with computer simulation based on results of earlier trials, illustrated with a lipodystrophy trial in HIV patients.

The designer of a clinical trial needs to make many assumptions about real-life practice based on prior knowledge. Simulation allows us to learn from experience by using the information obtained from a trial to improve the original estimators of population parameters. We propose using data from a previous trial to formulate assumptions that can be used to simulate trials and thus improve the design of new trials. To demonstrate our method, we used data from a real clinical trial which had been designed to evaluate cholesterol level changes as a surrogate marker for lipodystrophy in HIV patients. We were able to identify the optimal design that would have minimised the cost of a trial subject to a statistical power constraint which could then be used to design a new trial. In particular, we focused on three factors: the distribution of cholesterol levels in HIV patients, trial recruitment rates and trial dropout rates. We were able to verify our hypothesis that the total cost resulting from carrying out a clinical trial can be minimised by applying simulation models as an alternative to conventional approaches. In our findings the simulation model proved to be very intuitive and a useful method for testing the performance of investigators' assumptions and generating an optimal clinical trial design before being put into practice in the real world. In addition, we concluded that simulation models provide a more accurate determination of power than conventional approaches, thus minimising the total cost of clinical trials.

Sulfur-containing hetero-calix[4]pyrroles as mercury(II) cation-selective receptors: thermodynamic aspects.

Two sulfur-containing hybrid calix[4]pyrrole derivatives (III and IV) have been synthesized and fully characterized. Several analytical techniques (1H NMR, conductance measurements, UV-vis spectrophotometry, titration potentiometry, and titration calorimetry) have been used to assess the interaction between these hybrid calixpyrrole receptors and metal cations in acetonitrile and dimethylsulfoxide. The partition constants of calix[4]pyrrole, I, II, and IV in the acetonitrile-hexane solvent system and the solubilities of the ligands in various solvents at 298.15 K were determined. 1H NMR measurements reveal the sites of interaction of calixpyrrole ligands with metal cations in CD3CN. Conductance and UV-vis spectrophotometric measurements were performed to establish the composition of mercury(II) calixpyrrole complexes in acetonitrile at 298.15 K. Titration calorimetry was used to quantitatively assess Hg(II)-calixpyrrole interactions. Thus the thermodynamics of complexation of calixpyrrole ligands with the mercury(II) cation in acetonitrile at 298.15 K are reported. Potentiometric titrations were also used to establish the stepwise stability constants for the complexation of calix[3]thieno[1]pyrrole with the Hg(II) cation in acetonitrile at 298.15 K. The results show that replacement of one or more pyrrole units by thiophene rings in calix[4]pyrrole has tuned significantly the discrimination ability of these ligands between anions and enables the produced hybrid calixpyrroles to bind selectively with Hg(II) in acetonitrile. No interaction was observed between these ligands and other metal cations in acetonitrile.

A new calix[4]pyrrole derivative and its anion (fluoride)/cation (mercury and silver) recognition.

A new calix[4]pyrrole-based macrocycle, meso-tetramethyl-tetrakis{4-[2-(ethylthio)ethoxy]phenyl}calix[4]pyrrole, 7, has been synthesized and fully characterized. Unlike other calixpyrrole derivatives that show selective interaction with anions, calixpyrrole 7 described in the present work forms stable complexes with both metal cations and anions. The thermodynamics of complexation of this ditopic calixpyrrole derivative with metal cations (Hg2+ and Ag+) and the fluoride anion in nonaqueous solutions have been determined by titration calorimetry, and the host-guest composition has been investigated by using conductance measurements at 298.15 K. 1H NMR studies provide clear evidence about the sites of complexation of 7 with the ionic species, which show that the NH groups are taking part in the complexation of this ligand with the fluoride anion while the sulfur donor atoms are responsible for the interaction with metal cations. Using the present data on 7 and structurally related analogues (1-6), the complexation behavior is discussed comparatively from the thermodynamic point of view. Possessing four sulfur-containing pendent arms, 7 displays an enhanced hosting ability for Hg2+ in acetonitrile. As compared with 1, the calixpyrrole derivative, 7, shows a unique interaction with fluoride among the anions investigated in acetonitrile and dimethyl sulfoxide. As far as the fluoride complex is concerned, the medium effect is assessed in terms of the thermodynamics of the transfer of reactants and product from acetonitrile (reference solvent) to dimethyl sulfoxide.

Modified calix[4]pyrrole receptor: solution thermodynamics of anion complexation and a preliminary account on the phosphate extraction ability of its oligomer.

A modified calix[4]pyrrole, namely meso-tetramethyl-tetrakis-(4-hydroxyphenyl) calix[4]pyrrole, 1, has been synthesized and characterized. (1)H NMR investigations in various deuterated solvents seems to indicate that this receptor interacts with acetone-d(6). The solution thermodynamics of 1 in various solvents is reported. Complexation studies in CD(3)CN show that the NH and OH functionalities of 1 are the active sites of its interaction with the fluoride and the dihydrogen phosphate anions. The composition of the anion complexes was established through conductance measurements. In all cases, 1:1 complexes are formed. The thermodynamics of anion complexation in acetonitrile and N,N-dimethylformamide is discussed comparatively with previous reported data for the parent calix[4]pyrrole, 2, and these anions in these solvents. The medium effect on anion complexation is discussed in terms of the solvation properties of the reactants and the product in acetonitrile and N,N-dimethylformamide. An oligomeric material containing 1 as anchor group was synthesized and characterized by mass spectrometry. Preliminary studies have been performed to assess the extracting properties of this oligomer for the removal of phosphates from aqueous solutions. The effects of pH, temperature on the extraction of this anion salt from water, as well as the kinetics of the process (fast) were investigated.

Clinical trial optimization: Monte Carlo simulation Markov model for planning clinical trials recruitment.

INTRODUCTION: The patient recruitment process of clinical trials is an essential element which needs to be designed properly. METHODS: In this paper we describe different simulation models under continuous and discrete time assumptions for the design of recruitment in clinical trials. RESULTS: The results of hypothetical examples of clinical trial recruitments are presented. The recruitment time is calculated and the number of recruited patients is quantified for a given time and probability of recruitment. The expected delay and the effective recruitment durations are estimated using both continuous and discrete time modeling. CONCLUSION: The proposed type of Monte Carlo simulation Markov models will enable optimization of the recruitment process and the estimation and the calibration of its parameters to aid the proposed clinical trials. A continuous time simulation may minimize the duration of the recruitment and, consequently, the total duration of the trial.

Anion complexation by calix[3]thieno[1]pyrrole: the medium effect.

The interaction of calix[3]thieno[1]pyrrole, 1, and halide and dihydrogen phosphate anions in a variety of solvents (acetonitrile, propylene carbonate, N,N-dimethylformamide, and dimethyl sulfoxide) has been investigated through 1H NMR, conductance measurements, and titration calorimetry. 1H NMR measurements reveal the sites of interaction of the ligand with the anions in CD3CN while the composition of the complex was determined through conductance measurements. A quantitative assessment of anion-ligand interactions is provided. Thus the thermodynamics of complexation of 1 with halide and dihydrogen phosphate anions in dipolar aprotic media at 298.15 K is reported. These data are interpreted in terms of the thermodynamics of transfer of reactants and product from a reference solvent (acetonitrile) to other solvents. The crucial role played by the solvent on the ability of the ligand to interact with anions and on the composition of the complex is demonstrated.

New insights on anion recognition by isomers of a calix pyrrole derivative.

Two isomeric structures of meso-tetramethyltetrakis(3-hydroxyphenyl)calix[4]pyrrole, 4-alphaalpha betabeta and 4-alphabeta alphabeta, have been isolated and characterized by 1H NMR in different solvents (CD3CN, CD3OD, and DMSO-d6) at 298 K. Standard Gibbs energies of solution derived from solubility data in various solvents were used to calculate the transfer Gibbs energy, delta(t)G(o), of these ligands using acetonitrile as the reference solvent. These results are consistent with the 1H NMR studies in different media that show chemical shift changes observed in the resonances of the NH and the OH protons of these ligands. Solvate formation was observed when these isomers were exposed to saturated atmosphere of N,N-dimethylformamide, dimethyl sulfoxide and propylene carbonate. Anion interaction involving 4-alphaalpha betabeta and 4-alphabeta alphabeta was investigated by 1H NMR in CD3CN while the complex composition was assessed through conductance measurements. Significant differences are observed in the affinity of these ligands for anions as well as in the composition of the fluoride complexes. Thus 4-alphaalpha betabeta shows selectivity for H2PO4(-) in acetonitrile while its isomer 4-alphabeta alphabeta is selective for the fluoride anion. Again the complex composition is altered for the fluoride anion when complexed with 4-alphaalpha betabeta in acetonitrile (1:1 complex) relative to 4-alphabeta alphabeta in the same solvent. The latter isomer shows an enhanced hosting ability for this anion. Thus two anions are taken up per unit of ligand. The thermodynamics of complexation of H2PO4(-) and these ligands in acetonitrile is discussed, and the results are compared with those involving calix[4]pyrrole and this anion in this solvent. It is shown that the isomers interact with two H2PO4(-) anions while one calix[4]pyrrole unit interacts with this anion. This paper demonstrates for the first time that the enthalpy parameter may be a suitable reporter of the number of hydrogen bonds formed when calix[4]pyrrole and its derivatives interact with the dihydrogen phosphate anion in acetonitrile. In moving from acetonitrile to N,N-dimethylformamide, 4-alphaalpha betabeta is unable to enter complexation with most anions, except fluoride, with which the formation of a 1:2 (ligand:anion) complex is demonstrated. The rather versatile behavior of these receptors for anions is explained on the basis of 1H NMR evidence and solvation effects. These investigations highlight the importance of the medium effect on the stability of the complex and reflect the inherent nature of the solvent and its highly significant involvement in the complexation process.

Validation by simulation of a clinical trial model using the standardized mean and variance criteria.

OBJECTIVE: To develop and validate a model of a clinical trial that evaluates the changes in cholesterol level as a surrogate marker for lipodystrophy in HIV subjects under alternative antiretroviral regimes, i.e., treatment with Protease Inhibitors vs. a combination of nevirapine and other antiretroviral drugs. METHODS: Five simulation models were developed based on different assumptions, on treatment variability and pattern of cholesterol reduction over time. The last recorded cholesterol level, the difference from the baseline, the average difference from the baseline and level evolution, are the considered endpoints. Specific validation criteria based on a 10% minus or plus standardized distance in means and variances were used to compare the real and the simulated data. RESULTS: The validity criterion was met by all models for considered endpoints. However, only two models met the validity criterion when all endpoints were considered. The model based on the assumption that within-subjects variability of cholesterol levels changes over time is the one that minimizes the validity criterion, standardized distance equal to or less than 1% minus or plus. CONCLUSION: Simulation is a useful technique for calibration, estimation, and evaluation of models, which allows us to relax the often overly restrictive assumptions regarding parameters required by analytical approaches. The validity criterion can also be used to select the preferred model for design optimization, until additional data are obtained allowing an external validation of the model.

Cation/anion recognition by a partially substituted lower rim calix[4]arene hydroxyamide, a ditopic receptor.

The complexation ability of a partially substituted lower rim calix[4]arene hydroxyamide derivative, 25,27-bis[N-(2-hydroxy-1,1-bishydroxymethylethyl)amino- carbonylmethoxy]calix[4]arene-26,28-diol, 1, for cations and anions was investigated through (1)H NMR, conductometry, spectrophotometry, and calorimetry in dipolar aprotic media. (1)H NMR studies of 1 in the deuterated solvents (acetonitrile, methanol, and dimethylsulfoxide) reflect ligand-solvent interactions in methanol and dimethylsulfoxide. As far as the cations are concerned, a selectivity peak is found when standard Gibbs energies of complexation of 1 with cations (alkaline-earth, zinc, and lead) are plotted against corresponding data for cation hydration. This finding reflects the key role played by the desolvation and binding processes in the overall complexation of this receptor and these cations in acetonitrile. This is also interpreted in terms of enthalpy and entropy data. Factors such as, the nature and the arrangement of donor atoms in the hydrophilic cavity of the ligand on cation complexation process, are discussed. This paper also addresses anion complexation processes. It is found that 1 interacts through hydrogen bond formation with fluoride, dihydrogen phosphate, and pyrophosphate in acetonitrile and N,N-dimethylformamide. The thermodynamics associated with these processes is fully discussed taking into account literature data involving calix[4]pyrroles and these anions in these solvents. Previous work regarding the water solubility of these ligands is discussed. It is concluded that 1 behaves as a ditopic ligand in dipolar aprotic media.