The characterization results are used to predict the influence of the modification on membrane permselectivity. The competitive mass transfer of singly and doubly charged cations in the electrodialysis process is investigated in underlimiting and overlimiting currents. Electrodialysis desalination of a solution containing Na+/Ca2+ or H+/Ca2+ cations shows that the modification leads to an increase in membrane permselectivity to single-charged cations due to the repulsion of Ca2+ ions from the positively charged membrane surface. The permselectivity of the polyaniline-modified perfluorinated membrane to H+ in the mixture of H+/Ca2+ cations is observed in all current regimes.This work discusses the applicability of polyaniline-modified cation exchange membranes for the separation of monovalent/divalent cations by electrodialysis. A novel method of membrane modification directly in the electrodialysis unit is used to prepare permselective membranes. Complex characterization of the membranes before and after modification allows revealing the influence of membrane matrix on the modification efficiency. The characterization of the membranes includes determination of the diffusion permeability, specific conductivity and current–voltage curves in HCl, NaCl and CaCl Progress poses new challenges for industry and science, associated with a decrease in the ecological load on the environment and depleting the natural resources. The electromembrane technologies could respond to such challenges due to the possibility of engineer the closed water circulating systems, preparing the water with the required grade of purity, and separating mixed solutions ,2,3,4. TA quite efficient modifying agent for this aim is polyaniline (PANI) due to its high conductivity, chemical and thermal stability . The effThe main role in the properties of the PANI-modified ion exchange membranes plays the content and distribution of modifiers in the membrane phase. The properties of composites depend on the PANI synthesis conditions: concentrations of aniline and oxidant, synthesis duration, the nature of oxidant, background acid and solvent, presence of concentration and electric fields, etc. ,23,24,25The regularities of composites formation are mainly investigated for Nafion-type membranes due to the variety of their applications, such as membrane electrolysis, proton exchange membrane fuel cells, sensors and others ,28,29,30It is known that the ionic form of the membrane affects its transport properties ,32, but The objects of research were homogeneous perfluorinated MF-4SK  and heterogeneous polystyrene MK-40  membranes. Both membranes contained sulfonic acid groups to eliminate the influence of fixed ions on modification efficiency and transport properties. The heterogeneous polystyrene MA-41 membranes  containing quaternary amino-groups served as auxiliary membranes in the electrodialysis demineralization process.The MK-40 membrane consists of KU-2 ion exchange resin based on divinylbenzene crosslinked polystyrene and polyethylene as the inert binder. This membrane is designed for the solution treatment by electrodialysis ,34. The 3 solution, 10% H2O2 solution and distilled water, the duration of each stage was 3 h. The membrane was washed with distilled water between stages. The pretreatment of the heterogeneous membranes comprised the degreasing of the membrane surface by carbon tetrachloride and its successive immersion in ethanol, sodium chloride solutions with concentrations 300, 100 and 30 g/L and distilled water for 24 h in each step. Afterward, the membrane was placed in a 10% solution of HCl for 48 h and washed with distilled water.The conditioning of homogeneous membranes was performed by the thermal-oxidative method  and incl2 for 10 min, then for 1 A/dm2 for 120 min for the MK-40 membrane and 50 min for the MF-4SK one. Then membranes were washed with sulfuric acid solution and water. The composites, prepared under the current conditions, contain PANI in emeraldine salt form [CEMs were modified by the PANI directly in the electrodialysis unit . The celalt form . Before 2) [P) was calculated according to the formula:Vw is the volume of the chamber with water; C and C0 are current and initial concentrations of the solution, correspondingly; l and S are thickness and working area of the membrane. Using dilute solutions enables determining the rate of an increase in the solution concentration in the chamber water containing (dC/dt) from the slope of the kinetic dependency of the solution conductivity in this chamber K is the cell constant corresponding to the slope of the concentration—conductivity dependence C—1/R.The DP was measured in two chamber cells separated by the membrane under investigation (the membrane area was 21 cm2) . One cham) was calculated from the active part of the membrane resistance under alternative current measured by mercury contact method [R is the membrane resistance, the membrane working area S was 0.785 cm2. The samples were equilibrated with the studied solutions before measurements.The specific conductivity . The potential drop across the membrane understudy was measured using Ag/AgCl electrodes by the Keithley 2701 ethernet multimeter/data acquisition system . These electrodes were placed in the Luggin–Haber capillaries. The Luggin–Haber capillaries were installed at both sides of the membrane under study in its geometric center at a distance of about 0.5 mm from the surface. The measurements of CVCs for ion exchange membranes occur under conditions of the laminar solution flow with volume crossflow velocity equal to 14 mL/min. All the experiments were performed at least three times to average the results. The experimental error did not exceed 5%.The membrane behavior under conditions close to reality can be estimated by the voltammetry method. The CVCs of the initial and modified membranes were measured in solutions of HCl, CaCl2. CEMs were commercial MK-40 and MF-4SK membranes and composites on their base with the PANI (MK-40/PANI and MF-4SK/PANI); the anion exchange membranes were commercial MA-41 membranes. The modified membranes faced the counter-ions flux by the PANI layer. The distance between membranes in the electrodialysis unit was 0.9 mm, and the membranes were separated by the grids; the solution linear velocity was 0.02 m/s. The operating regime of the laboratory electrodialysis unit was identical to the working conditions of industrial electrodialysis units. The electrodialysis process was performed in a potentiostatic regime under 0.75, 1, 1.5, 2, 4 and 6 V per elementary cell. The concentrations of Na+ and Ca2+-ions at the inlet and outlet of the concentration and desalination tracts were controlled every 60 min by a Stayer ion chromatographer , H+-ions concentration was determined by pH-titration using the automated titrator EasyPlus titrator Easy Pro . The kinetic dependencies of the cation concentration during the electrodialysis of the mixed solutions  were used to calculate the main mass transfer characteristics  as follows:iJ is integral ion flux of i ions; ΔiC is changes of i ions concentration during the experiment; V is the volume of the desalination chamber; N is number of CEMs in the electrodialysis unit; F is Faraday constant; I is current intensity; n is a number of elementary cells in the electrodialysis unit; η is current efficiency; W is energy consumption for the treatment of 1 m3 of the solution; U is the voltage applied on the electrodialysis unit; q is solution volume velocity.The investigation of the electrodialysis demineralization process was performed in a laboratory electrodialysis unit equipped with hydraulic manifolds for concentration and desalination chambers. The characteristics of the electrodialysis unit were determined according to the method , which a2 solutions was performed. The characterization includes investigation of the concentration dependencies of the DP and conductivity, CVCs, SEM images of the membrane surface, as well as the estimation of transport-structural parameters and counter-ion transport number within an extended three-wire model.To reveal the influence of polyaniline surface layer on transport properties of CEMs with the different structures, the complex characterization of the membranes in NaCl, HCl and CaCl2 solutions for the initial and modified membranes. The DP values for the initial homogeneous MF-4SK membrane are higher than for the heterogeneous MK-40 one in all electrolyte solutions. Diffusion experiments for modified membranes are performed at the different orientations of the membrane towards the electrolyte flux (by modified and non-modified surfaces) due to their anisotropic structure. The asymmetry of diffusion characteristics for the MF-4SK/PANI membrane is not detected ; a, b and c are fractions of the current passing through the mixed, gel and solution channels, a + b + c = 1; d and e are fractions of the solution and gel in the mixed channel, d + e = 1. Considering the gel phase ideal selective, i.e., counter-ion transport number in gel phase equals 1, the counter-ion transport number in the membrane  has a higher value for the heterogeneous membrane than for the homogeneous one in all electrolyte solutions. It is concerned with the specific preparation technologies: the homogeneous membrane is the continuous selective conducting phase, while the heterogeneous membrane contains grains of ion exchange resin and polyethylene and free solution located at the junction between these polymers. Therefore, the value of the current transport through the gel phase is greater for homogeneous membranes. The conductivity concentration dependencies are used to estimate the transport-structural parameters of the extended tree-wire model by Equations (7)–(12), parameter values are presented in a parameter) in NaCl and CaCl2 solutions and portion of the solution in the mixed channel (d parameter) in acid solution. The value of the c parameter increases for all electrolyte solutions. The effect of modifier on transport properties and model parameters of the initial membrane is more pronounced in the case of the homogeneous membrane since it consists of flexible polymer chains, while the heterogeneous membrane has a rigid structure. According to the model, a modifier is incorporated into the gel phase. Accounting for the data presented in The modification of the membranes by the PANI leads to an increase in values of the intergel volume fraction for both types of membranes. This fact affects the current transport through the mixed channel . Calculation results are presented in + > Na+ > Ca2+. This order correlates with the increase in radii in hydrated form and hydration numbers of ions.The quantitative characteristic of ion exchange membrane selectivity in the solution of individual electrolytes is the true transport number of counter-ions. Value of c value. Positively charged emeraldine salt has an ion exchange function, so its presence in CEM leads to a decrease in the transport number of cations. Under the current preparation conditions, PANI content in the membrane is about 1 wt %, so the membrane retains cation exchange properties. The selectivity decrease is more pronounced in CaCl2 solution in comparison with HCl and NaCl solutions. It should be noted that obtained membranes have an anisotropic structure, while conductivity measurements were performed under alternative current. Retarding effect towards Ca2+-cations could be more pronounced under direct current when the PANI layer faces the cations flux.The modification leads to the decrease in the selectivity of the membranes, which correlates with the rise of the ilim) are higher in the solution containing HCl than in other solutions because of the abnormal mobility of hydrogen cations. On the whole, the ilim values in all solutions for the MF-4SK membrane are slightly higher than for the MK-40 one.The CVCs of the initial membranes are typical and have three regions : ohmic rilim values on the modified membrane surface, and the absence of the ilim on the non-modified surface . As it is expected, the current efficiency for Ca2+-ions exceeds the one for Na+ in the case of the initial MK-40 membrane at low potential per elementary cell (0.75–1.5 V). When the potential per elementary cell exceeds 2 V, the current fraction transferred by Na+-ions increases and the current efficiency for both cations is close. Similar results were observed for the MK-40/PANI membrane in NaCl/CaCl2 solutions, but in the low potential range, the difference in the current efficiency for Na+ and Ca2+ is smaller than for the MK-40 membrane. This effect can be attributed to the repulsion of doubly charged cations by the positively charged PANI layer on the surface of CEM. The total current efficiency for the initial and composite membranes is high and does not depend on the potential per elementary cell.2. The current is mainly transported by H+ ions in the investigated potential range due to the relay-race mechanism of its transfer in water solution  could be estimated as the ratio of fluxes of the different counter-ions divided on their equivalent concentrations in solutions fed to the inlet of the desalination tract.The main purpose of the work was to evaluate the possibility of the application of the PANI-modified CEMs for the separation of cations in the electrodialysis. The theoretical ratio of fluxes of doubly and singly charged cations in limiting conditions for ideally selective membrane (limiting permeability coefficient  formula :(14)P1/20−9 m2/s . PCa2+/H2 solution using initial membranes have shown that in the low potential range, Ca2+ flux significantly exceeds the Na+ flux. For example, the Ca2+/Na+ flux ratio is 2–3 for both types of membranes at 0.75 V per elementary cell due to the higher mobility of doubly charged ions in the solution. At higher potentials per elementary cell, the Ca2+/Na+ flux ratio decreases to 1 and almost achieves the theoretical value +/Mg2+ and discovered that increasing the current density (below the limiting condition) resulted in decreased transport number of Mg2+ and the permselectivity over Na+.thors of  investig2+/H+ solution equals 0.13, so the H+ flux should exceed Ca2+ one in 8 times. As can be seen from 2+ and H+ fluxes have close values for the initial MK-40 membrane at low potentials per elementary cell (Uel.c. < 1.5 V). At higher potentials permeability coefficient decreases to 0.6 but does not reach the theoretical value. After modification of the MK-40 membrane by the PANI, the dependence of Ca2+/H+ flux ratio rises on voltage per elementary cell. At low potentials, H+ flux through composite MK-40/PANI membrane is about two times higher than the Ca2+ one, which agrees with the estimation of counter-ion transport number within the extended three-wire model. At Uel.c. > 3 V flux ratio becomes similar to the initial MK-40 membrane . The ion fluxes become nevertheless almost equal with increasing current density.The limiting permeability coefficient in the mixed Camembrane b. The auThe presented data show that the PANI layer located on the surface of the heterogeneous membrane does not significantly affect the characteristics of the electrodialysis process. These results agree with the results of the investigation of physic-chemical characteristics of the membrane before and after modification. The expected decrease in doubly charged cations flux after modification by the PANI, however, is observed. The higher quantity of the PANI on the surface of CEM should enhance the permselectivity of the PANI modified CEMs.2 mixed solution using initial and modified membranes and HCl + CaCl2 solution using initial membrane are also close to the heterogeneous ones (2 mixed solution with the MF-4SK/PANI membrane (2+-ions essentially decreases in comparison to H+, unlike heterogeneous membranes and salt solutions.The results of the electrodialysis treatment of the mixed solutions using homogeneous initial MF-4SK and composite MF-4SK/PANI membranes are presented in ous ones a–c. Thermembrane d: curren2+/Na+ and Ca2+/H+ solutions. As for the current efficiency curves, flux ratios in salt solution are similar for both types of membranes before and after modification. One can see that in Ca2+/H+ solution, the Uel.c. < 1.5 V, while the opposite relation is observed for the MK-40 membrane. This may be due to the relay-race mechanism of proton transfer, which should be provided by the presence of free water. 2+ and H+ ions. It is revealed the relation between the structure and properties of membranes and the efficiency of the separation of Ca2+/H+ ions during the electrodialysis. The most significant differences are observed for the MF-4SK/PANI membrane during the electrodialysis of acid solution (2+ transfer in comparison with H+ and Na+ ions in the MF-4SK/PANI membrane is revealed. In contrast to the non-modified MF-4SK membrane, the double-/single-charged cations flux ratio achieves the limiting permeability value in a wide potential range for both Na+ and H+ counter-ions.solution b. A signSuch a result is obtained for the first time and has not been described in the literature. It is shown the applicability of composites on the basis of perfluorinated MF-4SK membranes and PANI for the separation of singly and doubly charged counter-ions by the electrodialysis. For the first time, it was shown that the permselectivity of the membrane could be observed not only in ohmic but in overlimiting operation regimes of the electrodialysis unit.2 solutions and their mixtures are investigated. The modification of the cation exchange membranes by polyaniline leads to the decrease of diffusion permeability and specific conductivity in all studies solutions. However, this effect is more significant for the modified homogeneous membrane than for the heterogeneous one. The diffusion permeability and specific conductivity of homogeneous MF-4SK membrane decrease after modification 2–3 times and 3–4 times, respectively. These characteristics for modified heterogeneous MK-40 membrane decrease 1.5 times and 1.4 times, correspondingly. The tree-wire model is used to calculate the counter-ion transport numbers for all samples. The decrease in the selectivity of the modified membranes in comparison with the initial ones is observed. The asymmetry of the current–voltage curves for modified homogeneous MF-4SK membrane is found, and the shape of the current–voltage curves depends on their orientation towards the counter-ion flow. Thus, the efficiency of modification of the cation exchange membrane by polyaniline substantially depends on the structural type of the membrane. In the case of a perfluorinated homogeneous membrane, the modification is more effective. The complex characterization of membranes can be used for the prediction of their permselectivity in the electrodialysis process.The present investigation has shown that the cation exchange membrane could be modified by polyaniline directly in the electrodialysis unit immediately before the electrodialysis separation of multicomponent solutions. The diffusion permeability, specific conductivity, current–voltage curves of the homogeneous and heterogeneous membranes in NaCl, HCl, CaCl2+/H+ fluxes through polyaniline-modified membrane equals 0.13, while for the initial membrane, this value varies in range 1.25–0.85. For the first time, it is shown that permselectivity of the membrane to singly charged cations in the mixture of singly/doubly charged cations could persist not only in underlimiting but also in overlimiting current regimes in potentials range 0.5–6 V per elementary cell. This result is obtained using polyaniline-modified homogeneous membrane in HCl/CaCl2 mixed solution.The competitive mass transfer of singly and doubly charged cations in the electrodialysis process with the initial and modified cation exchanges membranes is investigated. The increase in membrane resistance after modification negligible influences the energy consumption of the electrodialysis process. The ratio of Ca


The COVID-19 pandemic has had a significant impact on mental health at the level of the population. The current study adds to the evidence base by examining how the prevalence of psychological distress changed in Australia during the pandemic. The study also assesses the psychometric properties of a new single-item measure of mental distress included in a survey program conducted regularly throughout the pandemic. Data are from 1158 respondents in wave 13 (early July 2020) of the nationally representative Taking the Pulse of the Nation (TTPN) Survey. The questionnaire included the six-item Kessler Psychological Distress Scale (K6) and a new single-item measure of distress. Results show a significant increase in the prevalence of psychological distress in Australia, from 6.3% pre-pandemic to 17.7% in early July 2020  = 2.51 to 4.05). The new single-item measure of distress is highly correlated with the K6. This study provides a snapshot at one point in time about how mental health worsened in Australia during the COVID-19 pandemic. However, by demonstrating the accuracy of the new single-item measure of distress, this analysis also provides a basis for further research examining the trajectories and correlates of distress in Australia across the pandemic. The COVID-19 pandemic has had a significant impact on mental health at the level of the population, through both the direct effects of COVID-19  and the indirect effects associated with the policy responses used to contain the spread of the virus . In AThe current study examines data from the Taking the Pulse of the Nation (TTPN) survey which has tracked the economic, social and personal wellbeing, and attitudes of Australians over the course of the pandemic . The surScales assessing non-specific psychological distress have an important role in mental health research, surveillance/monitoring and clinical practice ,11,12. TWhile the K6 is a short scale, there are circumstances in which an even briefer measure of distress may be needed. For example, the cost and time needed to add multi-item scales of mental health or psychological distress to large epidemiological or omnibus panel surveys may be prohibitive, whereas the addition of a single item may be feasible . A very In general, would you say your mental health is:) found only moderate correlation with established mental health scales [Although these types of need have driven the development and use of ultra-short mental health measures ,31,32,33h scales . Howeverh scales ,29,30,32The need for an ultra-short measure of psychological distress in the TTPN survey was to balance the aim of regularly measuring key aspects of economic, social and personal wellbeing throughout the pandemic while minimising respondent burden during this stressful period. Therefore, the core measures in all content areas, including mental health, were restricted to a single-item measure. The new mental distress item was based on the K6 scale.Formally, the aims of the current study are: (i) to estimate the prevalence of high psychological distress in the Australian population, and among key subpopulations, during the COVID-19 pandemic using the K6, and to compare these with pre-COVID population estimates; and (ii) to assess the psychometric properties and the accuracy of a single-item measure of mental distress in comparison to the K6.OZInfo, the TTPN survey is based on a mixed sampling frame of phone interviews and online responses, with the same set of questions asked in both forms. Phone responses are recorded by the caller, whereas online respondents complete the responses themselves. Each wave recruits 1200 respondents from all states across Australia, although the number of responses from the Northern Territory are often tiny. The sample is stratified by age, gender, and location to be representative of the Australian population, with weights generated for each wave to better reflect the profile of the Australian population. The ethical aspects of the TTPN survey were approved by the Human Research Ethics Committee at the University of Melbourne, under the project title “Social and economic effects of COVID-19 on the Australian population” (Reference number: 2021-14006-14669-1).The data emanate from the Melbourne Institute’s TTPN survey, a repeated cross-sectional survey conducted in Australia since April 2020. The aim of the survey is to monitor key indicators of life in Australia such as mental distress, financial stress, satisfaction with Government policy responses, beliefs about the effect of pandemic, and labour force status. Conducted by marketing research company The current analysis draws on wave 13 of the TTPN conducted between 30 June 2020 and 3 July 2020. The wave 13 questionnaire included the six-item Kessler Psychological Distress Scale (K6)  (only inp < 0.001).Of the 1200 participants in wave 13 of the TTPN survey, 25 respondents (3.2%) had missing data on at least one of the K6 items (see (a)K6 scale(b)TTPN mental distress measureThe K6 is a well-established measure of distress and commonly used to identify serious mental illness . It provDuring the past week, about how often did you feel depressed or anxious?” with the same response options as for the K6. This item directly assesses feelings of anxiety or depression, which is consistent with the item content of the K6 [The TTPN single distress item was constructed for inclusion in each wave of the survey and designed to (i) be brief, (ii) have face validity and be readily interpretable, and (iii) be based upon the K6 measures. Thus, respondents were asked “f the K6 ,39. SimiIn addition to the measures of distress, the analyses consider age, sex, labour force status , and location of residence  given that these characteristics are available in the data and may be associated with distress.so sad that nothing could cheer you up?” whereas the matching item in the K6 refers to feeling “so depressed that nothing could cheer you up?”. Others have treated these items as similar in analysis [To provide a pre-COVID-19 comparison, we use data from the 2019 wave of the Household Income and Labour Dynamics in Australia (HILDA) Survey. The HILDA Survey is a longitudinal household panel survey that commenced in 2001 and, when weighted, provides a nationally representative estimate of Australian households, though underestimates new migrants and those living in very remote areas of the country. For more details of the HILDA Survey, see . The 201analysis . The othWe initially present unweighted descriptive statistics for the pre-COVID HILDA and TTPN samples, and compare labour force status in weighted analysis with the expectation that the TTPN survey will demonstrate a significant increase in unemployment associated with the COVID-19 pandemic. We then report results of a series of (weighted) simple logistic regression models, comparing the prevalence of high psychological distress across the two occasions, and stratified by key demographic characteristics to identify whether, and in which social groups, levels of psychological distress had worsened during the pandemic. A final (weighted using the TTPN Survey weights) logistic regression model includes all covariates.To evaluate the new single-item measure of mental distress, we directly compare a binary estimates of distress (weighted and unweighted) produced by the TTPN item with the standard K6 measure, and examine the correlation and Cohen’s Kappa coefficient. The predictive accuracy of the TTPN item was assessed by receiver operating characteristic (ROC) curve analysis, and examination of Area Under the Curve (AUC) . We repoThe final analyses present a series of random-effects logistic regressions to directly compare the two binary distress measures available for each participant . The test of the level-2 indicator evaluates the difference in the estimate of the prevalence of psychological distress derived from the two different measures within the same individuals, while the test of an interaction between the distress measure and each demographic or economic variable  assesses the consistency of the two measures within the different subpopulations.χ2 (1) = 0.01, p = 0.9), age group (χ2 (6) = 1.48, p = 0.96) and location (χ2 (1) = 1.10, p = 0.30) were similar in the 2019 and 2020 samples. There was, however, a significant difference in labour force status (χ2 (df = 2) = 181.70, p < 0.001), with estimated unemployment increasing from 2.7% of the population in 2019 to 12.0% in 2020.Characteristics of the analysis samples are presented in The weighted estimates of the prevalence of psychological distress in Australia from the two surveys, and by key characteristics, are presented in χ2 (1) = 10.19, p < 0.001), age category and timing (χ2 (2) = 9.28, p < 0.01) and labour force status and timing (χ2 (2) = 22.82, p < 0.001). A series of separate analysis found there were significant interactions between gender and timing  and the rest of Australia demonstrated no difference . A final logistic regression model controlling for all covariates continued to demonstrate a significant effect of timing .There was a strong positive correlation between the K6 scores and the TTPN distress item . In comparison, the correlation between each item within the K6 and the scale score constructed from the remaining K6 items (item-rest correlation) ranged between 0.72 to 0.84, with a mean of 0.79.none to little; 95% CI: 2.94–3.99), 4.1 , 4.1  and 6.3 .Using the standard cut-point on the K6 for comparison, the ROC curve presented in p = 0.017). Calculating the marginal probabilities showed that the estimated prevalence of distress derived from the two measures (K6 and the TTPN item) did not significantly differ for those aged 18 to 34 years  or those aged 36 to 64 years , but that the prevalence estimate derived from the TTPN item was significantly greater than from the K6 for those aged 65 years or older .Finally, a series of random-effects logistic models tested whether there were differences between the two estimates of distress derived for each individual from the TTPN item and the K6 scale. An initial model including all the covariates described in The aims of the current study were to estimate the prevalence of psychological distress in the Australian community during the COVID-19 pandemic and to assess the psychometric properties of a new single-item measure of mental distress. Our results indicate there was a significant increase in levels of likely serious mental illness in Australia, from 6.3% pre-pandemic to 17.7% in early July 2020. The survey was in the field after the restrictions associated with the first wave of COVID-19 had lifted, and just as the first signs of community transmission that would become the second wave in Australia were being observed in the state of Victoria. However, we find psychological distress was not elevated in respondents from Victoria compared to the rest of Australia.The current results are consistent with other Australian research using the K6, though based on a different methodology conducted at a similar time 17.1%) , but muc.1% , butOur analysis of the change in psychological distress in different subpopulations identifies three groups in which the increase was most pronounced. Consistent with other studies ,43, we fOur finding that distress increased more for men than women is contrary to most other research during COVID-19 . Consistsome of the time and all of the time response categories) results in the same classification decision as the recommended threshold of 18 on the K6 (distressed vs. not distressed) for 81% of respondents, and shows moderate sensitivity (0.71) and very high specificity (0.93). The Positive and Negative Predictive Values were broadly consistently with the sensitivity and specificity measures, respectively. These figures need to be interpreted in the context of the relatively low prevalence of distress in the population (17.6% in the current study according to the K6) which will deflate PPV and inflate NPV relative to samples in which the prevalence of distress is higher. Overall, the TTPN distress item is a useful addition to the researcher’s toolkit, providing an adequate measure of mental distress that can be used in circumstances where time is highly constrained but a measure of distress is needed. As described earlier, this may be the case when seeking to minimise respondent burden, when the costs of including a longer distress scale are prohibitive, or where the mode of administration preclude a longer questionnaire [There is a strong correlation (rho = 0.81) between scores on the single-item TTPN measure and the K6 scale, and moderate to high correspondence between these two measures of distress according to the ROC curve analysis with an AUC of 0.93 . The optionnaire ,26. HoweThere are several limitations of this study that need to be acknowledged. First, the comparison to pre-pandemic distress is based on data collected using a different methodology and recruitment methods. However, our estimates are consistent with other Australian studies  and loweThis study adds to the research literature demonstrating how the population’s mental health worsened during the COVID-19 pandemic. The increase was not uniform across all groups in society, and was most pronounced among men, young Australians, and those in employment. We also found that the single TTPN distress item provided a reasonable approximation of the estimate of distress generated by the K6. This analysis, therefore, provides the basis for future research drawing on the existing waves of the TTPN survey to examine trajectories and correlates of distress in Australia during the pandemic.


New approaches to assessing the “enzyme–ligand” complementarity, taking into account hydrogens, have been proposed. The approaches are based on the calculation of three-dimensional maps of the electron density of the receptor–ligand complexes. The action of complementarity factors, first proposed in this article, has been demonstrated on complexes of human dihydrofolate reductase (DHFR) with ligands. We found that high complementarity is ensured by the formation of the most effective intermolecular contacts, which are provided due to predominantly paired atomic–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized. An analytical docking algorithm based on the proposed receptor–ligand complementarity factors is proposed. At present, considerable experimental material has been accumulated on the chemical transformations of organic compounds. The presence of certain functional groups in the substrate allows chemists to assume the types of reactions, reagents, and conditions for carrying out the reactions to achieve the desired product. Nevertheless, the task of targeted synthesis is often complicated by the presence in the substrate and reagent of several functional groups capable of interacting with each other, the possibility of competing parallel reactions. Questions often arise as to which of them will prevail and how the process can be controlled to obtain the required product. A special case of interactions is enzyme–ligand complexation. The development of X-ray structural analysis of complexes makes it possible to freeze the structures of the complexes at the moment of interaction between the receptor and the ligand. Various docking techniques are being developed to model the structures of enzyme–ligand complexes but, nevertheless, they often give complexes that are very different from those found experimentally. Different scoring functions and binding energies do not allow the selection of the most correct structures of the complexes. Therefore, in this work, we tried to take a different path. We assumed that the interaction between the enzyme and the ligand, as a particular case of substrate–reagent interactions, obeys a certain law of complementarity to their electronic structures which dictates a completely definite orientation of the ligand in the receptor cavity.Here we must point out that the idea of complementarity is not new. It was first formulated by Paul Ehrlich in biology for antigen–antibody interactions . In physRecently, we investigated ,8,9 diffDihydrofolate reductase (DHFR) is one of the major enzymes determining intracellular metabolism. Briefly, under a cofactor nicotinamide adenine dinucleotide phosphate (NADPH) regulation, DHFR transforms folic acid taken from food to 7,8-dihydrofolate and 5,6,7,8-tetrahydrofolate (FH4) ,18. At tFor the complementarity assessment, complexes of human DHFR with ligands were taken from the Protein Data Bank ,11. ThesThen, we performed detailed enzyme–ligand complementarity assessment for the complexes with added hydrogen atoms. At that, hydrogens positions were optimized using hybrid QM/MM approach. The used optimization technique and electronic properties of the complexes have been described in .To estimate the electron density, we used the AlteQ method, which has proven itself well in predicting the electron density maps of a number of organic and inorganic compounds and determined using low temperature high resolution X-ray diffraction data ,14,15,16ρ) at an arbitrary mth point in the molecular space with coordinates N is the number of atoms in a molecule and A atomic increment in molecular electron density at the mth point of the molecular space, i-th sp-orbital, d-orbital, and the f-orbital of the A atom respectively, A atom, A atom and the mth point. If b] = 1/Å, [a] = e/Å3, and consequently [ρ] = e/Å3.In the AlteQ method, the electron density (mth point of the molecular space (Equations (3) and (4)):Therefore, we can estimate the electron density contributions of the ligand and the enzyme to the Three-dimensional maps of electron density represented as the density value at the lattice junctions of the cubic grid with the step 0.1 Å have been calculated for all complexes. All atoms  not belonging to the ligand molecule were referred to the enzymatic part (enzyme).It is obvious that the outer shell plays the most important role in the formation of covalent bonds and intermolecular contacts, therefore, first of all, we obtained the contribution of the outer shells (p-elements of the 1–3 periods (ligand atoms and near-ligand enzyme atoms are mostly s- and p-elements of the 1–3 periods), the contribution of the outer orbital of the A atom to the electron density at the mth point can be written as follows:For s- and The contribution of the inner shells –(11)):Therefore, analogously to the Equations (5) and (6) we can estimate the inner shells (mth points of the molecular space with 3). In other words, this space is the set of traditional ligand atomic basins—the term which is used in ‘Theory of Atoms in Molecules’ suggested by Richard F.W. Bader [First, detailed 3D electron density maps were calculated for the entire near-ligand space, where the electron density of the ligand is greater than 0.001 au , e-th enzyme atom and the l-th ligand atom, respectively, e-th enzyme atom and the l-th ligand atom, respectively.The first complementarity factor (CF1) has been suggested in ,8,9 and e-th enzyme atom and the l-th ligand atom, respectively.The second ):The number of electrons in the overlaps of the outer orbitals of the enzyme and the ligand equals (Equation (20)):The algorithm for determining overlap functions whose particular cases are ribed in .We estimated the “enzyme–ligand” overlaps in the complexes without hydrogens. It has been found that the overlaps All complexes showed very high complementarity of ligands and the enzyme structures without hydrogens to each other in the zones of intermolecular contacts  of CF2 and CF3 factors (R2(CF2) and R2(CF3)) in most cases are a little smaller than R2(CF1). Good correlations are observed for both cases, namely for the zones of intermolecular contacts  for both the published complementarity factor CF1 and the factor CF2 when the zones of intermolecular contacts  of the dependencies (12) CF3 = f(SUMRLRE) can be used as the criteria of complementarity of complexes with hydrogens, even for the zones of intermolecular contacts.The points with the maximum deviation of the predicted and observed CF3 factors CF3 )–CF3(predicted using Equation (12)), and laying above the black line in Since for all considered complexes the overlaps of inner orbitals are insignificant, then CF3≈CF4. However, CF4 factor is sensitive to the incorrect ligand pose with the pronounced overlaps of inner orbitals. This can be demonstrated by the example of complex 4kfj. We modified it by displacing the ligand in the receptor cavity by 0.45 angstroms so that the minimum distance between the contacting atoms becomes 1.55 Å. points values  and CF3 factor) was found. The relationship is presented in We collected data on the values of inhibitory concentrations (IC50) of eight ligands out the nine ligands presented in this article from the Binding Database in order to demonstrate experimental control. We found the negative decimal logarithm of the IC50 values; they are given in the Equations (12) and (14) can be transformed (Equation (25)).Then, designating (Equations (26) and (27))Analogously, based on the Equations (12), (15)–(17) we can determine CFka and CFkb-parameters that have been determined for the most effective ligands can be used to build a pattern of the electronic structure of the desired drug. This image can be presented in general form as follows (Equation (35)): Further, a new molecule can be superimposed on the given pattern until their maximum coincidence. In this case, we will be able to determine the most complementary position of the new ligand in the receptor cavity.Based on the dependency (12) and Equations (14)–(16) and knowing parameters of the Equation (12) determined for a concrete receptor, we can suggest an approach for an analytical solution of the problem of molecular docking.Consider the mth points that are located in the middle of the intermolecular contact of eth enzyme’s atom and lth ligand’s atom. Then the distance In the case when the mth point is closest to the atoms e and l and the contribution of neighboring atoms to the electron density at the mth point is much lower than the contributions of the atoms e and l, then for elements of 1–3 periods, including organogens, it is possible to write (Equations (36) and (37)):Then we can determine distances of the most effective contacts between atoms l and e in the “enzyme–ligand” complex based on the In the case of correct non-covalently bound complexes, both High correlation coefficients of dependences (12) show that in the formation of a complex, the most effective are intermolecular contacts which provide predominantly paired atom–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized, in which the contributions of neighbors to the mth point become comparable to the contributions of atoms e and l. Those interactions are carried out along lines  providing the maximum contribution of e and l atoms and the minimum contribution of neighbors covalently bound to e and l atoms.These regions of space are very close to the lines along which the maximum distance from atoms–neighbors is observed. This statement is in good agreement with the theory of Ronald Gillespie and Ronald Nyholm ,35 that On the example of the 1kms complex, Basically, these are the points responsible for the formation of the most effective interactions—hydrogen bonds O-H…O, N-H…O, etc. The contribution of neighbors in intermolecular interactions is noticeable in pi-stacking  and in C…H contacts, therefore the Equations (38)–(40) should give incorrect values for such intermolecular interactions and can only work for predicting the lengths of covalent C-C and C-H bonds, when at small distances from the nucleus  the electron density increases many times in comparison with the electron density of neighbors due to the exponential function of the electron density.CF1, CF3, and CF4 are given in Distances of the most effective contacts determined using Equations (38) and (40) and Hydrogen atoms are at the periphery of the molecule, in general, many N…N, N…O, O…O contacts are made through hydrogen atoms, i.e., they are N-H…N, N-H…O, N…H-O, O-H…O hydrogen bonds. The CF3 and CF4 factors take into account the presence of hydrogens, so the lengths of direct N…N, N…O, O…O contacts are best calculated from CF1 factor for the complex without hydrogens in the zone of intermolecular interactions. Thus, these CF1, CF3, CF4 factors are additional to each other. The obtained distances  and 4 ca(1)Computation of the distances (Equations (38)–(40)) of the most effective contacts and the most preferred for a given enzyme.(2)The construction of contact zones for the ligand and the enzyme; these zones determine the direction of intermolecular interactions between the ligand and the enzyme.eth atom. In order to find these zones, you need to find coordinates of points in the basin of eth atom ((3)In order to find the contact zones in the ligand, the same can be performed for the periphery ligand atoms.(4)The correct binding position of the ligand can then be determined from the condition of maximum overlap between the contact zones of the enzyme and the ligand.Therefore, analytical docking of a new ligand can be based on the estimation of preferred lengths of the most effective intermolecular contacts typical for the enzyme. Then the docking procedure is reduced to the following steps:points, can be estimated. After that, the Equation shown in The proposed docking algorithm based on the maps of the electron density of the ligands will make it possible to predict the structure of the receptor–ligand complexes. For the docked complexes of DHFR, having no overlaps of inner shells, the quality of the Equation (12) for CF3 or CF4 complementarity factors, namely R2/Npoints. We found that formation of an enzyme–ligand complex is based on the formation of the most effective intermolecular contacts, which provide predominantly paired atom–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized. Algorithm of analytical docking procedure based on the enzyme–ligand complementarity factors has been suggested.In this work, we suggested new approaches for assessment of enzyme–ligand complementarity. The approaches are based on the calculation of 3D maps of electron density of “receptor–ligand” complexes. The work of the complementarity factors was demonstrated on the complexes of human DHFR with ligands, taking into account hydrogens. For the first time, the possibility of overlapping inner orbitals was taken into account, which can later be used to discard incorrect docked structures. We found the relationship between experimental pIC50 values of ligands and the characteristic of the complementarity assessment, namely R2/N


To investigate the effects of temperature and hydration on the microstructure of polymer electrolyte membrane and the transport of water molecules and hydronium ions, molecular dynamics simulations are performed on Nafion 117 for a series of water contents at different temperatures. The interactions among the sulfonate groups, hydronium ions, and water molecules are studied according to the analysis of radial distribution functions and coordination numbers. The sizes and connectivity of water clusters are also discussed, and it is found that the hydration level plays a key role in the phase separation of the membrane. However, the effect of the temperature is slight. When the water content increases from 3.5 to 16, the size of water clusters in the membrane increases, and the clusters connect to each other to form continuous channels for diffusion of water molecules and hydronium ions. The diffusion coefficients are estimated by studying the mean square displacements. The results show that the diffusion of water molecules and hydronium ions are both enhanced by the increase of the temperature and hydration level. Furthermore, the diffusion coefficient of water molecules is always much larger than that of hydronium ions. However, the ratio of the diffusion coefficient of water molecules to that of hydronium ions decreases with the increase of water content. Polymer electrolyte membrane fuel cells (PEMFCs) have received particular attention, due to their renewable energy, zero emissions, high power density, high efficiency, low operating temperature and low noise advantages ,2. The p2O clustering, and the diffusion of H3O+ and H2O. Compared with Nafion, the shortened side-chain of PFSA membranes did not appreciably change the structural or dynamic properties of PFSA membranes, while increasing the temperature of the SSC membrane resulted in a much bigger increase in the proton and water diffusion coefficient than changing the side chain length. Cheng and Hong [Molecular dynamics (MD) simulations are ideal methods to investigate the microstructures and the physical/chemical properties of PEMs. Bahlakeh et al.  investigand Hong  studied and Hong . In the and Hong , the claand Hong ,28, monoand Hong , solvatiand Hong , differeand Hong ,32 and sand Hong ,34,35 onAlthough the hydrated polyelectrolyte membranes have been extensively studied using molecular dynamics simulations, the systematic research on the effects of hydration and temperature on the microstructure and transport properties of polyelectrolyte membranes is relatively rare. In the present work, molecular dynamics simulations on Nafion 117 system are performed at different hydration and temperature to investigate the effects on the microstructure and the mobility of the water molecules and hydronium ions, the simulation results are compared with relevant experimental and theoretical investigations.x = 7 and y = z = 1. In this work, each Nafion chain consisted of 10 monomers, so the n in The chemical structure of Nafion  is shownEb), angle-bending term (Eθ), torsion angle term (Eϕ) and out-of-plane bending term (Eχ), cross term (Ecross). The non-bond interactions including the van der Waals (vdW) term (Equation (3)) and the Coulombic term (Equation (4)) are used to describe the interactions between pairs of atoms that are separated by two or more intervening atoms or those that belong to different molecules.In this work, all the simulations were performed with the COMPASS II  force field ,39,40. I(a)MD simulation for 100 ps at 300 K in NVT ensemble.(b)MD simulation for 100 ps at 300 K in NPT ensemble.(c)The final structure of NPT MD simulation is heated from 300 K to 600 K, MD simulation is performed for 50 ps for every 100 K increase in temperature in the NVT ensemble.(d)The final structure of procedure (c) is cooled from 600 K to 300 K, MD simulation is performed for 50 ps for every 100 K decrease in temperature in NVT ensemble.(e)MD simulation for 100 ps at 300 K in NPT ensemble.The initial cells are first optimized to minimize their energies by means of the steepest descent method and the conjugate gradients minimization algorithms. After the optimization process, the following dynamics simulation procedures are performed:After repeating procedure (c) to (e) three times, the final structure was taken as the initial configuration for equilibrating procedures. Equilibrations using this configuration were carried out for 1 ns at 298 K, 323 K, and 353 K respectively, in the NPT ensemble. The equilibrating procedure was followed by 1ns NVE dynamic simulation at 298 K, 323 K, and 353 K, respectively, from which the trajectories were used for analyzing structural properties and dynamic properties. In the molecular dynamics simulation using the NVE ensemble, the energy of the system is conserved. This is very important and extremely necessary for the diffusion simulation. However, simulations in such an ensemble are not temperature controlled. The monitored, fluctuating temperatures in our NVE simulations for λ = 16 are shown in All MD simulations in this work were performed using Materials Studio 2017 program , three-dimensional periodic boundary conditions were applied, and time steps of 1 fs were used. Nose–Hoover thermostats and Berendsen barostats were used to control the temperature and pressure at the desired temperature and ambient pressure for all ensembles. The Ewald summation routine was used to calculate long-range electrostatic forces.Fully equilibrating the simulated cell is one of the crucial steps in any MD study. During the NPT simulations of equilibrating procedure in this work, the cell density was fluctuant. When the density remained almost unchanged and the fluctuation was slight, it indicated that the system was fully equilibrated. The densities in the course of the equilibration procedures are shown in In order to understand the microstructure of the hydrated membranes, it is necessary to look into the configurations obtained from the MD simulations. The snapshots of each system for λ = 3.5, 7, 10, 13 and 16 at the end of the simulations at 298 K are shown in r from a reference atom A, and can be calculated by Equation (5) [nB is the number of B atoms situated at a distance r in a shell of thickness dr from particle A, NB and V represent the number of B atoms in the system and the total volume of the system, respectively. The coordination numbers (CNs) are obtained by integrating the area under the corresponding RDFs to evaluate the correlation of different molecules or groups quantitatively [The RDF is defined as a measure of the probability of finding an atom B at a distance tion (5) .(5)gA-Btatively .w (RDFs between sulfur atoms of sulfonate groups and oxygen atoms of water molecules) for different water contents at 298 K, 323 K and 353 K are shown in w RDFs, the intense peaks occurred at about 3.72 Å, which means there is a hydration shell around the –SO3− at a distance of 3.72 Å from the sulfur atom. This is consistent with the previous findings [The RDFs of S-Ofindings ,15,16. W3- and hydronium ions were studied by the RDFs of S-OH (RDFs between sulfur atoms of sulfonate groups and oxygen atoms of hydronium ions) displayed in w RDFs, at about 3.72 Å, proving that the sulfonate groups attract both water and hydronium ions. However, the heights of S-OH RDFs are much greater than those of S-Ow RDFs, and not that sensitive to the water content, which is attributed to the strongly mutual attraction between the positively charged hydronium ions and the negatively charged sulfonate groups.The interactions of −SOThe CNs of water molecules and hydronium ions around the sulfur atoms are shown in The cursory visual inspection of the snapshots in The analysis of the cumulative fraction of the number of molecules in clusters confirms the conclusion of cursory visual inspection on the microstructure of the hydrated membrane, that the phase separation of the membrane is affected a lot by the hydration level. As the water content increases, the sizes of water clusters in the system increase, and the connection between clusters is improved, forming the continuous channels for transportation of water molecules and hydronium ions.ri (t) is the location of atom i at t time, N is the number of freely diffusing atoms in the system.The transport of water and hydronium are crucial for a polyelectrolyte membrane. In the classical MD simulations, the self-diffusion coefficients can be estimated by studying the mean square displacements (MSDs) ,44. The D can be calculated by Equation (7).According to the Einstein’s diffusion law, the self-diffusion coefficient a, according to Equations (6) and (7) the self-diffusion coefficient D can be easily estimated as:If we define the slope of the curve of MSD with time as The MSDs of water molecules and hydronium ions calculated from the final 1 ns of the dynamics simulation trajectories for different hydration levels at different temperatures are displayed in We can also discuss the above phenomenon more precisely in terms of the diffusion coefficients of water molecules and hydronium ions. The diffusion coefficients calculated from the linear regime of the MSD curves are shown in −5 cm2/s and 1.25 × 10−5 cm2/s at 298 K and 353 K for λ = 14 respectively [−5 cm2/s and 2.036 × 10−5 cm2/s for λ = 13 at the same temperature. This may be due to the periodic boundary conditions applied in our simulation, which is just an ideal treatment for an infinite system. The experimental results were obtained by describing the diffusion processes in a restricted geometry with ill-defined boundaries. However, the simulated diffusion coefficients of hydronium ions are significantly smaller than the experimental ones, e.g. the simulated results are 1.649 × 10−6 cm2/s at 298 K and 2.953 × 10−6 cm2/s at 353 K for λ = 16, while the experimental values are 7 × 10−6 cm2/s and 10 × 10−6 cm2/s at 303.15 K and 353.15 K, respectively [From ectively  and Cui ectively . This isMolecular dynamics simulations were performed on Nafion 117 polymer electrolyte membrane for λ = 3.5, 7, 10, 13, 16 at 298 K, 323 K and 353 K, to determine the effects of temperature and hydration on the microstructure and transport properties of a polyelectrolyte membrane. The simulated results of the densities of the membrane at 298 K agree well with the experimental and theoretical results. The density gradually decreases with the increase of water content at the same temperature, and this can be attributed to the swelling of the membrane due to the increasing hydration level. For the same hydration level, the density decreases with the increase of temperature, and this is a reflection of the thermal expansion of the membrane.w and S-OH appear at about 3.72 Å, the difference is that the heights of the first peaks of S-OH RDFs are much larger than those of S-Ow RDFs, suggesting that the interaction of hydronium ions and the sulfonate groups is much stronger. The CNs of water molecules and hydronium ions around the sulfonate groups in the first solvation shell are obtained by integrating the area under the corresponding RDFs. Comparing the CNs of water molecules and hydronium ions for the different membranes at the same temperature or for the same membrane at different temperatures, it can be seen that when the CN of water molecules is higher, the CN of hydronium ions is lower, vice versa. There seems to be a competition between water molecules and hydronium ions for the space close to sulfonate groups.For all hydration levels, the first peaks of RDFs of S-OWater clusters are characterized with a cutoff radius of 3.5 Å, and all of the clusters are found in the simulated membranes. The analysis of the cumulative fraction of the number of molecules in clusters suggests that the phase separation of the membrane depends a lot on hydration. However, the influence of temperature on the structure is found to be insignificant. As the hydration level increases from λ = 3.5 to 16, the clusters become bigger until they connect with each other to become a larger cluster spanning the entire system. This is consistent with the results of the cursory visual inspection of the snapshots of the simulated membranes.The diffusion coefficients of water molecules and hydronium ions are calculated according to the MSDs. Because of the strong electrostatic interaction of the hydronium ions with the sulfonate groups, the diffusion coefficient of hydronium ions is always much smaller than that of water molecules, when compared at the same temperature and hydration level. The mobility of water molecules and hydronium ions are both strengthened by the increased hydration level, however, the mobility of hydronium ions is more sensitive. Increasing the temperature also promotes the diffusion of water molecules and hydronium ions. Due to the polymer blockage and the electrostatic interaction between the hydronium ions and the sulfonate groups, the calculated diffusion coefficients of water molecules and hydronium ions in hydrated membranes are quite smaller that in bulk waterThe calculated diffusion coefficients in the present study compare well with those reported in other works; however, they differ from the experimental data. The diffusion coefficients of water molecules are larger than the experimental values, while those of hydronium ions are smaller. This is due to the unavoidable disadvantages of MD simulation, and the same trend has also been reported in literature.


The following sentence should be added to the end of the first paragraph of the Acknowledgments section: “Collection and export of fecal samples was also facilitated by the Filoha Hamadryas Project with the generous permission of the Ethiopian Wildlife Conservation Authority.”Volume 4, no. 4, e00271-19, 2019,


Psoriasis is an immune-mediated chronic inflammatory skin disease with extracutaneous manifestations, that affects about 1–3% of the world’s population. The disease is not life-threatening, but the disability which comes with it is comparable to the disability caused by other serious chronic diseases, such as oncologic or cardiovascular disease. Several risk factors, such as infections, stress, smoking, excessive alcohol consumption and genetic predisposition have been involved in inducing psoriasis. Smoking status is a risk factor for many chronic diseases, including psoriasis. Moreover, recent studies have tried to answer the question of whether smoking also influences the response to biologic therapy in patients with psoriasis. Through the current study, our intention is to find out how smoking affects the response to biologic treatment. A hospital-based cross-sectional, observational, non-interventional, retrospective study of moderate and severe psoriasis patients receiving biologic treatment was developed. Two groups were defined based on smoking status: group 1 included smokers (more than 10 cigarettes/day) and former smokers, and group 2 included non-smokers. The data that resulted from the analysis of the cohort of patients demonstrate that smoking status does not affect the response of biologic therapy in patients with moderate and severe psoriasis. Psoriasis is an immune-mediated chronic inflammatory skin disease with extracutaneous manifestations that affects about 1–3% of the world’s population . SmokingIt is well known that smoking influences the onset of the disease and also the evolution, but the effect of smoking on psoriatic patients being on biologic therapy is under debate. Some studies have suggested that smoking is associated with an increased severity of psoriasis and diminished treatment responses among patients with psoriasis ,6.Psoriasis is a chronic inflammatory disease that is mediated by Th1 and Th17 helper T cells. Smoking produces free radicals that may activate signaling pathways such as the mitogen-activated kinase, nuclear factor B and Janus kinase-STAT pathways. Byproducts from smoking, such as nicotine and dioxin, activate T cells that produce interleukin-12 (IL-12), interleukin-17 (IL-17) and interleukin-23 (IL-23), which are also involved in the pathogenesis of psoriasis . BecausePlaque psoriasis can be classified as mild, moderate or severe on the basis of the degree of erythema, desquamation and infiltration, and the extent of body surface area involvement . A wide The majority of patients with mild-to-moderate psoriasis is capable of adequately controlling the disease solely with topical medications or phototherapy. Biologic agents, administered as monotherapy or in combination with other topical or systemic drugs, have a high benefit-to-risk ratio and, due to this situation, are a welcome addition to the psoriasis management armament ,21. TherA hospital-based cross-sectional, observational, non-interventional, retrospective study of moderate-to-severe psoriasis patients receiving biologic treatment was developed by the authors for which it received approval from the Ethics Committee. For requiring biologic therapy, patients must fulfill the inclusion criteria established in our country. A total of 109 patients from the Second Dermatology Department of the Colentina Clinical Hospital in Bucharest were enrolled in the study. These patients were included in the National Registry of Dermato-Venereological Diseases and signed the informed consent to participate in the study. These patients were treated with all types of biologic therapy available in our country: TNF-α inhibitors , adalimumab , infliximab  and their biosimilars); IL-12/23 inhibitor ) and IL-17 inhibitors , ixekizumab ).Detailed information about smoking history as well as the clinical severity of psoriasis were noted at baseline and one year after treatment initiation. The clinical severity of psoriasis was assessed using PASI score and the smoking history was assessed using a questionnaire of smoking habits. The Dermatology Life Quality Index score (DLQI) was used to quantify the impact of the disease on life quality. Two groups were defined based on the smoking status: group 1 included smokers (more than 10 cigarettes/day) and former smokers and group 2 included non-smokers. Smoking status included three categories: have never smoked, current smoker and former smoker. The latter includes those who had stopped smoking at least one year before being interviewed for this study. We used the Statistical Package for the Social Sciences (SPSS) software version 23 for Windows program. used for statistical data analysis. In order to determine the statistical significance we used Paired Samples T Tests and Chi-Square Tests.Most patients in the study group have at least one comorbidity. These range from psoriatic arthritis, which is the most common, to metabolic syndrome, cardiovascular disease, obesity and diabetes mellitus. However, these variables were not followed in the current study.Inclusion criteria were: evidence of a personally signed and dated informed consent form indicating that the subject has been informed of all pertinent aspects of the study; adult patients aged ≥18 years at the time of screening; clinical diagnosis of psoriasis and anatomopathological diagnosis confirmation; diagnosis of severe psoriasis defined as PASI > 10; eligible for biologic treatment according to the National Protocol for Biological Therapy in psoriasis and to Summary of Product Characteristics; biologic-naive patients; smokers who smoke >10 cigarettes daily for smokers group (group 1) or non-smokers for non-smoking group (group 2); capable of understanding and completing questionnaires.Exclusion criteria were: failure to adequately cooperate in the study; hypersensitivity to the active substances or to any of the excipients; active infections, sepsis or risk of sepsis; positive pregnancy test, breast feeding or considering becoming pregnant during the study; significant drug or alcohol abuse.The objectives of the study were to determine the percentage of patients achieving a PASI 100 response (complete remission) in group 1 versus group 2 after one year of biologic therapy, to determine the quality of life among enrolled patients after one year of biologic therapy and to evaluate the impact of smoking over the treatment outcome.The study reported data obtained from 46 females and 63 males, with the mean age of 52.59 for females and 50.06 for males. From the total of 109 patients, 68 patients (62.38%) of the group live in the urban areas and 41 patients (37.61%) come from rural areas. It was observed that the percentage of smoking patients of the total number of patients in the study was 46.8%. Former smokers accounted for 7.3% and non-smokers accounted for 45.9%, which means that group 1 included 54.1% of patients and group 2 included 45.9% of patients.The percentages of patients who obtained complete remission one year after the initiation of biologic therapy were 50.2% in group 1, respectively 49.2% in group 2.The mean PASI at the initiation with biological therapy in group 1 was 19.87, with a median of 20.15, compared to the mean PASI of 20.66 in group 2, with a median of 21. The mean PASI after one year of biologic therapy in group 1 was 2.20, with a median of 0, compared to 1.29, the mean PASI after one year of biologic therapy in group 2, with a median of 0 .p value is 0.921 (>0.05), which means that there is no statistically significant difference between the two groups.To evaluate the clinical response to biologic therapy, a variable called DIFFPASI was calculated. DIFFPASI represents the difference between the initial PASI and PASI after one year of biologic therapy. The value of this variable is 18.44 in group 1, which means that the PASI score decreased by an average of 18.44 in group 1. The value of DIFFPASI is 18.57 in group 2, which means that PASI score decreased by an average of 18.57 in the non-smokers group . p valuep value was 0.09 (>0.05), which means that there was no statistically significant difference between the two groups.The percentages of patients who obtained a DLQI score of 0 after one year from the initiation of biologic therapy are 44.4 for group 1 and 55.6 for group 2, respectively. Regarding the DLQI score, it had a value of 22.3 at baseline with a median at 22.5 in group 1 versus the value of 22.3 with a median of 22 in group 2. The mean value of DLQI score one year after initiation of biologic therapy in group 1 was 2.22 with a median of 0 compared with the mean value of DLQI score of 0.7 with a median of 0 in group 2 . To compGroup 1 and group 2 were each divided into two subgroups by gender: females and males. Other data that emerged from the statistical analysis of the two subgroups are the following: firstly, the age at which the disease was diagnosed in the women subgroup ranged from 3 years to 64 years, with a median of 38.5 years and a mean age of 39.5 and the age at which the disease was diagnosed in the men subgroup ranged from 7 years to 75 years, with a median of 35 years and the mean age of 37.5 . In the p value of 0.02 (p < 0.05).Secondly, the mean age in women subgroup at which patients started smoking is 24.08 years, with a median of 21.5 years compared to the mean age in the men subgroup, which is 19.61 with a median of 18 years . This meThirdly, regarding the smoking period, in the female subgroup the mean smoking period is 27.19 years versus 26.58 years in the male subgroup .Another result that emerged was that the average number of cigarettes smoked per day was 14.42 in women subgroup compared to 16.52 in men subgroup . From thPsoriasis is one of the many diseases associated with smoking and patients may be more motivated to consider quitting because of it than in other invisible skin health problems. The harmful influence of smoking is related to the induction of inflammatory mediators involved in the pathogenic phenomena of the skin of patients with psoriasis. Questioning smoking in psoriasis patients and supporting smoking cessation can help reduce the impact of smoking on psoriasis.Our cohort was balanced, with a comparable number of patients in the two groups. Regardless of the smoking status, all the patients suffered from moderate or severe psoriasis.In this study, the gender difference in the age of onset of psoriasis revealed an earlier onset of the disease in the male population. However, most patients developed psoriasis before the age of 40. In addition, in the male population, the onset of smoking was statistically significant earlier, compared to the female population, but men smoke for a shorter period of time than women; this was a counterbalance in terms of the higher number of cigarettes smoked per day by the female population.The data resulted from the analysis of this cohort demonstrate that smoking status does not affect the response of the biologic therapy in patients with moderate and severe psoriasis and similar results were obtained in many studies ,27,28,29Currently, there is no consensus on the impact of smoking on the therapeutic response in patients with psoriasis, which means firstly that medical data are insufficient and secondly reveals the difficulty of this topic. Numerous meta-analyzes have tried to elucidate this unknown fact, but the final results have not been consistent. On the one hand, there are authors who reported that smoking influences the therapeutic response in patients and postulated that smokers were less likely to show disease improvement in the disease at 6 months after treatment with biologic agents than non-smokers , and, onA recent meta-analysis published in 2020 suggests that the number of reports is limited and more studies are needed to confirm the effects of smoking and smoking cessation on the therapeutic response in patients with psoriasis .Medical data is limited on this subject and more studies are needed to establish the effects of smoking regarding the therapeutic response in patients with moderate and severe psoriasis in treatment with biologic therapy.However, the harmful effects of smoking are undeniable. These are found and can influence both the etiopathogenesis of psoriatic disease and the evolution, severity and treatment of this condition. In this study we tried to evaluate the effects of smoking on the group of patients in our hospital.The data that resulted from the analysis of the cohort of patients demonstrate that smoking status does not affect the response of biologic therapy in patients with moderate and severe psoriasis.Regardless of how smoking influences the therapeutic response of patients with biological therapy, it is clearly proven that smoking is involved in the pathogenesis of psoriasis, both as a trigger for the disease and as an aggravating factor. Thus, doctors have the duty to advise and encourage the patient to quit or reduce smoking, this being an essential step in the management of the disease.This result obtained in our study is sustained by many studies in the specialized literature. However, more studies with as many patients as possible are needed to reach a unanimous final conclusion.


The level of pain in the same time frame decreased to an average of 29%. The severity of pain 6 months after the beginning of treatment positively correlates with the number of injections per joint (0.63), the total amount of drug administered in milliliters (0.62), and the volume of drug administered monthly per joint (0.50). Limitations: In some studies, the patient groups were heterogeneous in terms of diagnosis. The studies varied depending on the joint into which the HA was administered. The synthesized studies differed with regard to the method of measuring the mandible abduction amplitude. Conclusions: The increase in the amplitude of mandibular abduction was expressed as the quotient of the mean values during the observation periods, and the initial value was achieved in all study groups, and in the linear regression model, it was 0.5 mm on average per month. Multiple administrations of the drug may reduce the analgesic effectiveness of the treatment.Objectives: The purpose of this systematic review with meta-analysis is to identify clinical studies concerning the impact of intra-articular administration of hyaluronic acid (HA) on mandibular mobility and to make an attempt at determining the efficacy of HA in this indication. Methods: The review included primary studies involving groups of at least 10 patients who were diagnosed with pain in the temporomandibular joint and who were injected with hyaluronic acid as the only intervention. The outcomes pursued were changes in mandibular mobility and pain intensity. Four databases of medical articles were searched, including PubMed and BASE. The risk of bias was assessed using the Cochrane methodology tools. The therapy‘s efficacy was calculated in the domains of mandibular abduction, protrusive movement, lateral mobility, and pain relief. For these values, the regression and correlation with variables characterizing the interventions were analyzed. Results: In total, 16 reports on 20 study groups with a total of 1007 patients qualified for the review. The mean effectiveness in the domain of mandibular abduction over the 6-month follow-up period was 122% of the initial value, and the linear regression model can be expressed as 0.5 The mandible’s movement is caused by the contraction of numerous muscles that operate the paired temporomandibular joints (TMJs). Restrictions in the mobility of the mandible can be a consequence of TMJ pain, classified in accordance with, among others, the International Classification of Orofacial Pain, 1st edition (ICOP) . There iThe administration of HA into the TMJ cavity is a surgical procedure that does not require hospitalization, same as arthroscopy; multiple synovial fluid replacements, e.g., arthrocentesis; additional puncture into a peripheral vein, such as therapy with blood products; or administration of drugs with many known side effects, for instance, intra-articular corticosteroid therapy . The absThe purpose of this systematic review with meta-analysis is to identify clinical studies on the impact of intra-articular administration of HA on mandibular mobility and make an attempt to determine the efficacy of HA in this indication.The inclusion and exclusion criteria of studies from the review were determined in accordance with the PICOS methodology, the name of which is an acronym for the following  8]. For. For8]. The selection of search engines was made in accordance with the recommendations of Gusenbauer et al. of 2020 regarding the selection of search systems for the purposes of systematic reviews and meta-analyses . Of the The queries resulting from the previously determined eligibility criteria were expressed in the form of appropriate strings, slightly different for each search engine . All datκ), according to the formula:p0 is a relative observed agreement among raters and ep is a hypothetical probability of chance agreement [The selection of studies was made in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyzes (PRISMA) methodology . PRISMA greement .In case of contradictory opinions, the given paper was processed further. The full-text evaluation was prepared by the same authors, and in the event of a possible discrepancy in decisions at this stage, the final judge was to be the next author (M.S.), but this was not the case during the selection process.All data coming from the reports were then extracted without the use of automation tools. Author M.C. and an independent individual not belonging to the authors’ group (see: Acknowledgements) collected the data autonomously. Another author (K.C.) verified the correctness of the extracted data.The following data were extracted from the reports:(1) First author of the report; (2) year of publication of the report; (3) designation of the study group; (4) type of administered HA; (5) amount of HA administered, ml per injection; (6) number of HA applications per joint; (7) total amount of HA administered, ml per joint; (8) total duration of therapy, weeks; (9) mean HA treatment interval, weeks; (10) mean amount of HA administered monthly, ml per joint; (11) other interventions in the study group; (12) study group size; (13) diagnosis according to ICOP; (14) number of joints treated; (15) number of right joints treated; (16) number of left joints treated; (17) mean number of joints treated per patient; (18) mean initial pain value on the Visual Analogue Scale (VAS); (19–25) mean VAS pain value at 1, 2, 3, 4, 5, 6, and 12 months; (26) mean initial mouth opening without pain; (27–33) mean pain free mouth opening after 1, 2, 3, 4, 5, 6, and 12 months; (34) mean initial unassisted mouth opening; (35–41) mean unassisted mouth opening after 1, 2, 3, 4, 5, 6, and 12 months; (42) mean initial assisted mouth opening; (43–49) mean assisted mouth opening at 1, 2, 3, 4, 5, 6, and 12 months; (50) mean initial protrusion movement; (51–57) mean protrusive movement after 1, 2, 3, 4, 5, 6, and 12 months; (58) mean initial painful joint side movement; (59–65) mean painful joint side movement after 1, 2, 3, 4, 5, 6, and 12 months; (66) mean initial movement to the healthy side; (67–73) mean healthy side movement after 1, 2, 3, 4, 5, 6, and 12 months; (74) mean initial movement to the right; (75–81) mean right movement after 1, 2, 3, 4, 5, 6, and 12 months; (82) mean initial movement to the left; (83–89) mean left movement after 1, 2, 3, 4, 5, 6, and 12 months.Variables numbered from 1 to 17 characterize the study groups. Variables from 26 to 49 correspond to the primary outcomes set out in the PICOS criteria of this systematic review. The values of the variables 18–25 and 50–89 constitute secondary outcomes. In the absence of data for the desired observation period, data for the closest period of time were entered, if available. In the absence of other data, the fields of the summary table were left blank, and individual barrage values were not taken into account in the course of the meta-analysis.The risk of bias in randomized controlled trials was assessed using “A revised Cochrane risk-of-bias tool for randomized trials” (RoB 2) . In non-e) was calculated according to the formula:v0 is the baseline value and xv is the value x months after the therapy initiation.For the change in pain intensity and all indicators of mandibular mobility, the coefficient of effectiveness  maximal mandibular abduction; (2) range of mandibular protrusive movement; (3) the range of lateral mobility of the mandible; (4) joint pain. In the above-mentioned domains, the relative coefficients of the opening efficiency, protrusion, and lateral mobility, as well as changes in the level of pain, were taken into account, independent of the absolute values of individual variables. In the case of several measurement methods in (1) domain, the maximum unassisted opening of the mouth was included in the synthesis, and in its absence, the maximum abduction of the mandible without pain. The maximum assisted opening was only taken into account in the absence of both of the above-mentioned measurements. Due to the assessment of the lateral mobility range of the mandible in some studies, taking into account the healthy and the diseased side, and in others the right and left side of the body, the arithmetic mean of the effectiveness for lateral movements was calculated according to the formula:R2.Meta-regression analysis was performed for each of the domains. The fitted regression models are shown as trend lines in graphs showing the change in treatment effectiveness over time. This analysis, apart from determining the averaged effectiveness of therapy with intra-articular injections of HA, allowed for the indication and an attempt to interpret the outliers. The coefficient of determination was denoted as r) were calculated and presented in the form of a matrix. To calculate the t-score (t) of each correlation, the following formula was used:n is a sample size. Test probability (p) was calculated using the two-tailed Student distribution. The adopted significance level was α = 0.05.The correlation was searched between data items (5)–(10), (12), (14), (17), the initial values of variables, and efficiencies in domains (1)–(4) after 1 and 6 months. In case of the unknown value of the variable after 6 months, the value after 12 months was given for the purposes of this analysis, and in the absence of both, the closest. Coefficients with more than half of the missing data were discarded. To determine the correlation, Pearson’s correlation coefficients , studying the relevant guidelines, carrying out exercises in the form of pilot reviews, and conducting other systematic reviews ,24,25,26κ = 0.82, which is determined as strong, but not very strong, convergence [The individual stages of study selection in accordance with the PRISMA methodology are presented in vergence . In ordevergence . UltimatThe reports describing the studies qualified for the systematic review are summarized in The risk of bias was assessed using the RoB 2 tool for randomized controlled trials and is presented in Full consistency was achieved in the data extracted independently by two investigators. The values of variables extracted from the reports and processed for the purposes of this synthesis  are presented in 2 = 17%; black line).2 = 48%) to the linear regression model expressed by the formula:Changes in the mouth opening range in the course of individual treatments (crosses) and as the mean (dots) are shown in 2 = 62%) fit of the linear regression model (black line) to the mean of the values for individual studies (dots). The trend lines for studies with a longer observation period have a very similar course to this model. This model can be expressed by the formula:The values of the mandible’s protrusive movement amplitude in the studies of individual authors (crosses) are plotted on the coordinate axis in 2 = 57%) into the linear regression model expressed by the formula:The averaged values of the lateral mandible mobility for individual tests are shown graphically with crosses . Most ofp < 0.05), are bolded.The above-mentioned data characterizing the study groups and the values of the variables concerning pain and mandibular mobility were examined for the presence of correlation. The results are presented in The severity of pain 6 months after the beginning of treatment positively correlates with the number of injections per joint (0.63), the total amount of drug administered in milliliters (0.62), and the volume of a drug administered monthly per joint (0.50). These correlations are not strong, but they are enough to raise suspicions whether repeated interventions reduce the analgesic effect, i.e., fewer administrations of HA may be more effective in managing TMJ pain. The intensity of pain after 6 months, starting from the beginning of the therapy, depends, to some extent (0.45), on the initial pain value as well. This means that the stronger the pain before starting the treatment, the greater its severity may remain during the follow-up period.p coefficient did not reach the required value. However, the possibility that a greater supply of HA reduces the effectiveness of the therapy should be taken into account.There is a stronger than the previous negative correlation (−0.70) of the increase in the maximum opening of the mouth after 6 months from the beginning of the treatment with the initial values of this variable. Therefore, it can be assumed that the stronger the restriction of vertical mobility of the mandible, the greater the effect in this domain will be achieved by HA therapy. Weak negative correlations are observed between the increase in the maximum mandibular abduction after six months from the beginning of treatment and the following values: (1) ml of the drug per injection (−0.34); (2) number of injections per joint (−0.24); (3) total amount of drug administered per joint expressed in ml (−0.30); (4) the number of ml of drug administered monthly per joint (−0.28). For the four correlations mentioned, the Good treatment results in the reports of Macedo De Sousa et al. may result from simultaneous splint therapy . Romero-The efficacy of intra-articular injections of HA versus the use of stabilizing splints was compared by Korkmaz et al. . These aYilmaz et al. compared the effectiveness of HA therapy with the effectiveness of HA administration preceded by arthrocentesis in groups of patients diagnosed with disk displacement with and without reduction. In both diagnoses, the effectiveness of the combination therapy was noticeably higher .Macedo De Sousa et al. demonstrated a better immediate effect of HA supply combined with splint therapy than splint therapy alone or intra-articular PRP injections combined with splint therapy . This efBatifol et al. demonstrated higher effectiveness of HA therapy compared to intra-articular injections of corticosteroids in the 6-month follow-up period, both in the domain of mandibular mobility and pain . SimilarIn some studies, patient groups were heterogeneous in terms of diagnosis. In future reviews involving subsequent reports, it is worth considering subgrouping patients with the following diagnoses in particular: (1) disk displacement with reduction; (2) disk displacement without reduction; (3) osteoarthritis, and (4) degenerative joint disease. Such division may help in assessing the effectiveness of HA therapy in individual patient groups.The studies differed in the compartment of the joint into which the HA was administered. Assessment of the effectiveness of HA therapy depending on the administration to the upper or lower part of the joint cavity (above or below the articular disc) is a significant problem and should be considered in future systematic reviews based on more reports. In addition, various drugs containing HA in different concentrations have been used, which further complicates the formulation of strong conclusions.In this systematic review, baseline values for the variables of mobility and pain were taken as reference values. The efficacy of HA treatment compared to alternative therapies was addressed in the discussion. More high-quality studies comparing HA treatment with placebo with alternative treatments are needed, especially arthrocentesis and intra-articular administration of blood products.The synthesized studies differed with regard to the method of measuring the amplitude of the mandible abduction. The authors of this systematic review are not aware of any studies indicating the most appropriate method of measuring this value. For the purposes of the synthesis, it was assumed that in the case of varying methods of measuring the extent of mandible abduction, the maximum value of the opening that is unsupported manually should be used, and then the value of the maximum pain-free mouth opening. Only in the absence of the above-mentioned data, the value of the manually assisted opening of the mouth was used.Only the reports published in English were eligible for systematic review.Due to the transparency and repeatability of the selection process, it was decided to search only the databases with free access. This could have resulted in the omission of reports indexed only in commercial databases, in particular those kept by publishers.The effectiveness of the administration of hyaluronic acid into the temporomandibular joints’ cavities, used as monotherapy, was assessed in 20 study groups with a total of over 1000 patients. The increase in the amplitude of mandibular abduction was expressed as the quotient of the mean values during the observation periods, and the initial value was achieved in all study groups, and in the linear regression model, it was 0.5 mm on average per month. The increase in the mouth opening range is probably inversely proportional to the initial value of this parameter. The mean value of pain in the temporomandibular joints decreased in each of the study groups over the course of the therapy. Multiple administrations of the drug may reduce the analgesic effectiveness of the treatment.