Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10 g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfully manufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

Hyperglycemia screening based on survey data: an international instrument based on WHO STEPs dataset.

BACKGROUND: Hyperglycemia is rising globally and its associated complications impose heavy health and economic burden on the countries. Developing effective survey-based screening tools for hyperglycemia using reliable surveillance data, such as the WHO STEPs surveys, would be of great importance in early detection and/or prevention of hyperglycemia, especially in low or middle-income regions. METHODS: In this study, data from the nationwide 2016 STEPs study in Iran were used to identify socioeconomic, lifestyle, and metabolic factors associated with hyperglycemia. Furthermore, the ability of five commonly used machine learning algorithms (random forest; gradient boosting; support vector machine; logistic regression; artificial neural network) in the prediction of hyperglycemia on STEPs dataset were compared via tenfold cross validation in terms of specificity, sensitivity, and the area under the receiver operating characteristic curve. RESULTS: A total of 17,705 individuals were included in this study, of those 29.624% (n = 5245) had (undiagnosed) hyperglycemia. Multivariate logistic regression analysis showed that older age (for the elderly group: OR = 5.096; for the middle-aged group: OR = 2.784), high BMI status (morbidly obese: OR = 3.465; obese: OR = 1.992), having hypertension (OR = 1.647), consuming fish more than twice per week (OR = 1.496), and abdominal obesity (OR = 1.464) were the five most important risk factors for hyperglycemia. Furthermore, all the five hyperglycemia prediction models achieved AUC around 0.70, and logistic regression (specificity = 70.22%; sensitivity = 70.2%) and random forest (specificity = 70.75%; sensitivity = 69.78%) had the optimal performance. CONCLUSIONS: This study shows that it is possible to develop survey-based screening tools for early detection of hyperglycemia using data from nationwide surveys, such as WHO STEPs surveys, and machine learning techniques, such as random forest and logistic regression, without using blood tests. Such screening tools can potentially improve hyperglycemia control, especially in low or middle-income countries.

Mortality rate of people exposed to Mustard Gas during Iran-Iraq war in Sardasht, Iran: a 32 years retrospective cohort study.

BACKGROUND: Mustard gas (MG) is one of the most widely used chemical weapons in the past century. However, little information exists concerning long-term mortality from MG exposure. In this study, we investigated mortality rate among civilian people exposed to MG during Iran-Iraq war in Sardasht in Iran after 32 years.  METHODS: In this retrospective cohort study, data of people exposed to MG in Sardasht in 1987 were extracted from the Veterans and Martyr Affair Foundation of Iran up to March 20, 2019. Mortality rate, cumulative mortality and standardized mortality ratio with 95% confidence interval were calculated to explain mortality in the cohort, and then compared with general Iranian population. Cox regression analysis was used to indicate factor affecting the risk of death in the cohort.  RESULTS: Out of 1,203 exposed people at the beginning of the period, 148 people died by the end of the study, with an average age of 66.42 at the time of death. Total person-years of the people up to end of the study were 38,198.63 and mortality rate was equal to 387 per 100,000 persons-years. Total number of observed deaths was less than expected death and the all-cause standardized mortality ratio (SMR) was determined as 0.680 (95% CI: 0.574 - 0.798). Cause-specific SMR showed that observed death due to respiratory diseases was higher than expected (SMR: 1.75) (95% CI: 1.145 - 2.569). The results of univariate and multivariate cox regression analysis showed that increasing age and having severe late complications in lung were associated with increased risk of death among people in the cohort. CONCLUSION: In general, this result indicated that acute exposure to MG, even without wearing protective clothing and masks, could not increase all-cause mortality after 32 years if accompanied by special and ongoing care for those exposed.

Decreased in-hospital mortality associated with aspirin administration in hospitalized patients due to severe COVID-19.

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.

Mental disorders pattern in staff of a military unit in Iran: the role of metabolic syndrome on latent class membership.

INTRODUCTION: Mental disorders are among the most prevalent health problems of the adult population in the world. This study aimed to identify the subgroups of staff based on mental disorders and assess the independent role of metabolic syndrome (MetS) on the membership of participants in each latent class. METHODS: This cross-sectional study was conducted among 694 staff of a military unit in Tehran in 2017. All staff of this military unit was invited to participate in this study. The collected data included demographic characteristics, anthropometric measures, blood pressure, biochemical parameters, and mental disorders. We performed latent class analysis using a procedure for latent class analysis (PROC LCA) in SAS to identify class membership of mental disorders using Symptom Checklist-90. RESULTS: Three latent classes were identified as healthy (92.7%), mild (4.9%), and severe (2.4%) mental disorders. Having higher age significantly decreased the odds of belonging to the mild class (adjusted OR (aOR = 0.21; 95% confidence interval (CI): 0.05-0.83) compared to the healthy class. Also, obesity decreased the odds of membership in mild class (aOR = 0.10, 95% CI: 0.01-0.92) compared to healthy class. On the other hand, being female increased the odds of being in severe class (aOR = 9.76; 95% CI: 1.35-70.65) class in comparison to healthy class. CONCLUSION: This study revealed that 7.3% of staff fell under mild and severe classes. Considering educational workshops in the workplace about mental disorders could be effective in enhancing staff's knowledge of these disorders. Also, treatment of comorbid mental disorders may help reduce their prevalence and comorbidity.

Promising effects of atorvastatin on mortality and need for mechanical ventilation in patients with severe COVID-19; a retrospective cohort study.

PURPOSE: Considering the anti-inflammatory effect of atorvastatin and the role of medical comorbidities such as hypertension and coronary artery disease on the prognosis of the COVID-19 patients, we aimed to assess the effect of atorvastatin add-on therapy on mortality caused by COVID-19. METHODS: We conducted a retrospective cohort study, including patients who were hospitalised with confirmed diagnosis of severe COVID-19. Baseline characteristics and related clinical data of patients were recorded. Clinical outcomes consist of in-hospital mortality, need for invasive mechanical ventilation and hospital length of stay. COX regression analysis models were used to assess the association of independent factors to outcomes. RESULTS: Atorvastatin was administered for 421 of 991 patients. The mean age was 61.640 ± 17.003 years. Older age, higher prevalence of hypertension and coronary artery disease reported in patients who received atorvastatin. These patients have shorter hospital length of stay (P = .001). Based on COX proportional hazard model, in-hospital use of atorvastatin was associated with decrease in mortality (HR = 0.679, P = .005) and lower need for invasive mechanical ventilation (HR = 0.602, P = .014). CONCLUSIONS: Atorvastatin add-on therapy in patient with severe COVID-19 was associated with lower in-hospital mortality and reduced the risk of need for invasive mechanical ventilation which supports to continue the prescription of the medication.

A Multi-variate Mathematical Model for Simulating the Granule Size Distribution in Roller Compaction-Milling Process.

Granule size distribution (GSD) is one of the critical quality attributes in the roller compaction (RC) process. Determination of GSD for newly developed pharmaceutical compounds with unknown ribbon breakage behaviors at the RC milling step requires a quantitative insight into process parameters and ribbon attributes. Despite its pivotal role in mapping the process operating conditions to achieve desired granule size, limited work has been presented in literature with a focus on RC-milling modeling. In this study, a multi-variate mathematical model is presented to simulate the full size-distribution of granulated ribbons as a function of ribbon mechanical properties. Experimental data with a lab-scale oscillating milling apparatus were generated using ribbons made of various powder compositions. Model parameters were determined by fitting it to experimental data sets. Parameters obtained from the first step were correlated to ribbon Young's modulus. The model was validated by predicting GSD of data that were excluded in model development step. Predictive capabilities of the developed model were further explored by simulating GSD profiles of a granulated pharmaceutical excipient obtained at three different conditions of a real-scale Gerteis RC system. While maintaining the milling operating conditions similar to the lab-scale apparatus (i.e., screen size and spacing, and low rotor speed), the proposed modeling approach successfully predicted the GSD of roller compacted MCC powder as the model compound. This model can be alternatively utilized in conjunction with an RC model in order to facilitate the process understanding to obtain granule attributes as part of Quality-by-Design paradigm.

Association between passive smoking and cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: The association between passive smoking (PS) and cardiovascular disease (CVD) has not yet been fully clarified. OBJECTIVE: This meta-analysis was performed to evaluate the association between PS and the incidence of CVDs and mortality due to CVD. METHODS: PubMed/Medicine, Science Direct, Scopus, Web of Knowledge, and ProQuest were searched to identify observational studies that met the inclusion criteria without time, language, age, gender, ethnicity, and design restrictions until July 30, 2018. In case-control studies, relative risk (RR) with 95% confidence interval (CI) was calculated for the relationship between PS and CVD incidence. Also, in cohort studies, hazard ratio (HR) with 95% CI was calculated for the relationship between PS and CVD mortality. RESULTS: Eighteen studies (10 cohort and 8 case-control studies) were included with 10,672 participants (2,542 cases and 8,130 controls) in case-control studies and 2,313,935 participants in cohort studies. This meta-analysis in case-control studies revealed that the PS could increase the risk of CVD incidence by 28% (adjusted RR = 1.28 [95% CI 1.09, 1.50]), where the highest risk was associated with those who were exposed to second-hand smoke at home and at work (Adjusted RR = 1.41 [95% CI 0.73, 2.70]). Also, the meta-analysis in cohort studies indicated that PS was associated with a 12% higher increase in the risk of CVD mortality (Adjusted HR = 1.12 [95% CI 1.06, 1.20]) with the highest risk of mortality being observed for those who were exposed to second-hand smoking at home, work, and public places (Adjusted HR = 1.26 [95% CI 1.13, 1.40]). CONCLUSIONS: PS is significantly associated with an increased risk of incidence and mortality of CVD.

Determination of pegfilgrastim aggregates by size-exclusion high-performance liquid chromatography on a methacrylate-based column.

A size-exclusion high-performance liquid chromatographic method using a methacrylate-based column was developed, validated and implemented for the determination of pegfilgrastim aggregates. The samples were directly injected into a TSKgel G4000PWXL column (7.5 mm × 300 mm, 10 µm, <500 A°) with a mobile phase of 100 mM phosphate, pH 2.5. Detection was made at 215 nm and analyses were run at a flow-rate of 0.6 ml/min at 10 °C. Vortex-mixing of samples produced oligomers, however, very high molecular weight aggregates were formed at high temperatures. The method exhibited linearity over the concentration range of 0.1-14 mg/ml for pegfilgrastim monomer and high molecular weight aggregates with a correlation coefficient of greater than 0.99. The method was specific and sensitive, with a lower quantification limit of 0.1 mg/ml and a detection limit of 0.02 mg/ml. Over 1200 samples were analyzed by the present method without significant change in the column performance.

Validation of the Persian version of the Daily Spiritual Experiences Scale (DSES) in Pregnant Women: A Proper Tool to Assess Spirituality Related to Mental Health.

Assessing spirituality in healthy pregnant women may lead to supportive interventions that will improve their care. A psychometrically valid measure such as the Daily Spiritual Experiences Scale (DSES) may be helpful in this regard. The current study sought to adapt a Persian version of DSES for use in pregnancy. A total of 377 pregnant women were recruited from three general hospitals located in Tehran, Iran. Administered scales were the DSES, Duke University Religion Index, Santa Clara Strength of Religious Faith scale, and Depression Anxiety Stress Scale, as well as demographic measures. Reliability of the DSES was tested using Cronbach's alpha for internal consistency and the intraclass correlation coefficient (ICC) for test-retest stability. Scale validity was assessed by criterion-related tests, known-groups comparison, and exploratory factor analysis. Participant's mean age was 27.7 (4.1), and most were nulliparous (70%). The correlation coefficient between individual items on the scale and the total score was greater than 0.30 in most cases. Cronbach's alpha for the scale was 0.90. The ICC for 2-week test-retest reliability was high (0.86). Relationships between similar and dissimilar scales indicated acceptable convergent and divergent validity. The factor structure of the scale indicated a single factor that explained 59% of the variance. The DSES was found to be a reliable and valid measure of spirituality in pregnant Iranian women. This scale may be used to examine the relationship between spirituality and health outcomes, research that may lead to supportive interventions in this population.

Gonadectomy reduces the density of androgen receptor-immunoreactive neurons in male rat's hippocampus: testosterone replacement compensates it.

BACKGROUND: In the present study, the role of gonadectomy on memory impairment and the density of androgen receptor-immunoreactive neurons in rats' hippocampus as well as the ability of testosterone to compensate of memory and the density of androgen receptors in the hippocampus was evaluated. METHODS: Adult male rats (except intact-no testosterone group) were bilaterally castrated, and behavioral tests performed 2 weeks later. Animals bilaterally cannulated into lateral ventricles and then received testosterone (10, 40 and 120 µg/0.5 µl DMSO) or vehicle (DMSO; 0.5 µl) for gonadectomized-vehicle group, 30 min before training in water maze test. The androgen receptor-immunoreactive neurons were detected by immunohistochemical technique in the hippocampal areas. RESULTS: In the gonadectomized male rats, a memory deficit was found in Morris water maze test on test day (5th day) after DMSO administration. Gonadectomy decreased density of androgen receptor-immunoreactive neurons in the rats' hippocampus. The treatment with testosterone daily for 5 days attenuated memory deficits induced by gonadectomy. Testosterone also significantly increased the density of androgen receptor-immunoreactive neurons in the hippocampal areas. The intermediate dose of this hormone (40 µg) appeared to have a significant effect on spatial memory and the density of androgen receptor-immunoreactive neurons in gonadectomized rats' hippocampus. CONCLUSIONS: The present study suggests that testosterone can compensate memory failure in gonadectomized rats. Also testosterone replacement can compensate the reduction of androgen receptor-immunoreactive neurons density in the rats' hippocampus after gonadectomy.

Rapid formulation assessment of filgrastim therapeutics by a thermal stress test.

The biosimilar versions of recombinant methionyl human granulocyte colony-stimulating factor (rh-Met-G-CSF, filgrastim) are now widely available. Because changes to the formulation often lead to subtle differences, there is a critical need to define techniques to test and insure the quality of these products. The present study was designed to compare formulation and thermal stress stability of filgrastim products. The formulation ingredients including acetate, polysorbate 80, and sorbitol were determined using state-of-the-art validated analytical methods. The formulation pH and osmolality were also measured. Moreover, the stability profiles of 8 filgrastim products using thermal stress at 57 °C for 4 h were assessed by size-exclusion high-performance liquid chromatography (SE-HPLC) and in vitro biological assay. The products had different stability profiles. More stable products were within the specification for formulation and less stable products were beyond the specification limits. Altogether, the results suggest that a short-time stress study at 57 °C and analysis of filgrastim by SE-HPLC could unveil formulation problems and is potentially useful for comparability studies.

Tacrolimus-induced cholestatic hepatotoxicity after renal transplantation: a case report.

BACKGROUND: In this manuscript, we report a case of tacrolimus-associated hepatotoxicity in a kidney transplant recipient. CASE PRESENTATION: In this case report, a 56 years old Arab male patient who received a kidney transplant presented with icterus, weakness, and lethargy two weeks after transplantation and tacrolimus initiation. In laboratory analysis hyperbilirubinemia and a rise in hepatic enzymes were observed. All possible causes of hepatotoxicity were examined. The panel for infectious causes was negative. Drug-induced liver injury was diagnosed. The patient's immunosuppressive regimen was changed to a cyclosporine-based regimen and after this change bilirubin and hepatic enzymes decreased and the patient was discharged without signs and symptoms of hepatitis. CONCLUSION: It seems that the patient's hyperbilirubinemia was due to tacrolimus, and the patient's bilirubin decreased after stopping tacrolimus.

A 39 Year mortality study of survivors exposed to sulfur mustard agent: A survival analysis.

Background: The primary objective of this study was to analyze the long-term survival of 48,067 chemical warfare survivors who suffered from pulmonary, cutaneous, and ocular lesions in the decades following the Iran-Iraq war. Methods: The data for this study were obtained from the Veterans and Martyr Affair Foundation (VMAF) database. The survivors were divided into two groups based on whether they were evacuated/admitted (EA) to a hospital or not evacuated/admitted (NEA) to a hospital. The proportional hazard (PH) assumption for age categories, gender, exposure statuses, and eye severity was not satisfied. Therefore, we used a Generalized Gamma (GG) distribution with an Accelerated Failure Time (AFT) model for analysis. Results: The study included a total of 48,067 observations, and among them, 4342 (9.03 %) died during the study period. The mean (SD) age of the survivors was 55.99 (7.9) years. The mortality rate increased with age, and higher rates were observed in males. Survival probabilities differed significantly among age categories, provinces, lung severity, and eye severity based on log-rank tests (p-value<0.05 for all). The GG model results showed that higher age and being male were associated with a shorter time to death. The study also found that the mortality rate was significantly higher in the EA group compared to the NEA group. Conclusion: The present study showed no significant difference in survival time between the EA and NEA groups. The findings suggest that pulmonary lesions caused by mustard gas are more likely to be fatal compared to skin and eye lesions. The results also indicate a potential association between survival time and the severity of lung damage.

Correlation between socio-demographic characteristics, metabolic control factors and personality traits with self-perceived health status in patients with diabetes: A cross-sectional study.

Purpose: This study aimed to assess the relationship between metabolic control factors, socio-demographic characteristics, personality traits, and self-perceived health status in diabetes. Methods: This cross-sectional study included 318 patients with type 1 and 2 diabetes (DM). Participants completed a questionnaire-based survey, which included the NEO Personality Inventory-Revised to measure five personality dimensions and the SF-12 survey to assess self-perceived health status. Binary logistic regression was performed to analyze the data, with socio-demographic characteristics, clinical data, and nutrition status as independent variables, and self-perceived health status (categorized as poor or good condition) as the dependent variable. Unadjusted and adjusted binary logistic regression analyses were used to examine the association between personality traits (high vs. low) and metabolic control factors (good control vs. bad control) with health status scores. Results: 60.7% of the participants with diabetes in the study described their health as "good." The results indicated that female gender (OR: 0.314, 95%CI: 0.105-0.938, P = 0.038), age > 60 years (OR: 0.263, 95%CI: 0.117-0.592, P = 0.001), comorbidities (OR: 0.314, 95%CI: 0.178-0.556, P = 0.001), DM complications (OR: 0.531, 95%CI: 0.337-0.838, P = 0.007), diabetic neuropathy (OR: 0.562, 95%CI: 0.356-0.886, P = 0.013), and diabetic ulcer (OR: 0.130, 95%CI: 0.023-0.747, P = 0.022) were independent variables associated with a "poor" health status. However, regular physical activity (OR: 3.144, 95%CI: 1.209-8.175, P = 0.019) and a healthy nutritional diet (OR: 2.456, 95%CI: 1.421-4.245, P < 0.001) were associated with a higher likelihood of a "good" self-perceived health status. Conclusion: Preventive programs and interventions aimed at improving self-perceived health among patients with diabetes should focus on increasing regular physical activity and promoting a healthy nutritional status. These actions should be particularly targeted towards female and older patients with higher neuroticism traits.

Evaluation of the safety and efficacy of biosimilar recombinant growth hormone in children with growth hormone deficiency: non-inferiority, randomized, parallel, multicentric and Phase III trial.

OBJECTIVES: This study is designed in order to compare the efficacy and safety of recombinant human growth hormone (rhGH) with the reference brand. METHODS: According to the inclusion criteria, 85 people in 13 Iranian centers were randomly selected to receive biosimilar Somatropin (Somatin®) (44 people) and reference Somatropin (Norditropin®) (41 people) at a dose of 35 µg/kg/d, seven days/week for 12 months. The primary outcomes included height velocity (HV) was measured during 12 months of treatment. RESULTS: The two intervention groups' Height changes were similar. The mean HV was 10.96 cm/year in the biosimilar group and 10.05 cm/year in the reference groups after 12 months. Estimates of the lower bounds of 95% CI for mean height differences in the biosimilar intervention group compared to the reference intervention group did not exceed the 2 cm margin. Therefore, the non-inferiority of biosimilar intervention compared to the brand product is verified. Common ADRs in both groups were nausea in two patients (2.4%), diarrhea in two patients (2.4%), increased body temperature in one patient (1.2%), and headache in one patient (1.2%). CONCLUSIONS: The finding of this study indicated that Somatin® and Norditropin® have comparable efficacy and safety profiles. CLINICAL TRIAL REGISTRATION: www.IRCT.irIRCT20171122037571N1.

Microparticle separation using dielectrophoresis-assisted inertial microfluidics: A GPU-accelerated immersed boundary-lattice Boltzmann simulation.

In this study, the migration of microparticles towards the inertial equilibrium positions in a straight microchannel with a square cross section in the presence of an inhomogeneous oscillating electric field was examined. The dynamics of microparticles were simulated using the immersed boundary-lattice Boltzmann method of fluid-structure interaction simulation. Moreover, the lattice Boltzmann Poisson solver was applied to calculate the electric field required for calculation of the dielectrophoretic force using the equivalent dipole moment approximation. These numerical methods were implemented on a single GPU coupled with the AA pattern of storing distribution functions in memory to speed up the computationally demanding simulation of microparticles dynamics. In the absence of an electric field, spherical polystyrene microparticles migrate to four symmetric stable equilibrium positions corresponding to the sidewalls of the square cross-sectional microchannel. The equilibrium distance from the sidewall was increased by increasing the particle size. The equilibrium positions near electrodes disappeared and particles migrated to the other equilibrium positions far from the electrodes by the application of the high-frequency oscillatory electric field at voltages beyond a threshold value. Finally, a two-step dielectrophoresis-assisted inertial microfluidics methodology was introduced for particle separation based on the crossover frequencies and the observed threshold voltages of different particles. The proposed method exploited the synergistic effect of dielectrophoresis and inertial microfluidics methods to remove their limitations, allowing the separation of a broad range of polydisperse particle mixtures with a single device in a short time.

Design and Fabrication of a High Performance Microfluidic Chip for Blood Plasma Separation: Modelling and Prediction of System Behaviour via CFD Method.

This paper presents a single-step microfluidic system designed for passive separation of human fresh blood plasma using direct capillary forces. Our microfluidic system is composed of a cylindrical well between upper and lower channel pairs produced by soft photolithography. The microchip was fabricated based on hydrophobicity differences upon suitable cylindrical surfaces using gravitational and capillary forces and lateral migration of plasma and red blood cells. The plasma radiation was applied to attach the polymeric segment (polydimethylsiloxane (PDMS)) to the glass. Meanwhile, Tween 80 was used as a surfactant to increase the hydrophobicity of the lateral channel surfaces. This led to the higher movement of whole blood, including plasma. Fick's law of diffusion was validated for this diffusion transfer, the Navier-Stokes equation was used for the momentum balance, and the Laplace equation was utilized for the dynamics of the mesh. A model with high accuracy using the COMSOL Multiphysics software was created to predict the capillary forces and chip model validation. RBCs (red blood cells) were measured by the H3 cell counter instrument, by which 99% plasma purity was achieved. Practically, 58.3% of the plasma was separated from the blood within 12 min. Correlation between plasma separation results obtained from software and experimental data showed a coefficient of determination equal to 0.9732. This simple, rapid, stable, and reliable microchip can be considered as a promising candidate for providing plasma in point-of-care diagnostics.

Assessment of drought conditions and prediction by machine learning algorithms using Standardized Precipitation Index and Standardized Water-Level Index (case study: Yazd province, Iran).

Drought as a natural phenomenon has always been a serious threat to regions with hot and dry climates. One of the major effects of drought is the drop in groundwater level. This paper focused on the SPI (Standardized Precipitation Index) and SWI (Standardized Water-Level Index) to assess meteorological and hydrological drought, respectively. In the first part, we used different time frames of SPI (3, 6, 12, and 24 months) to investigate drought in Yazd, a dry province in the center of Iran for 29 years (1990-2018). Then, in the second part, the relationship between SPI and SWI was investigated in the three aquifers of Yazd by some rain gauge stations and the closest observation wells to them. In addition to using SPI and SWI, we also used different machine learning (ML) algorithms to predict drought conditions including linear model and six non-linear models of K_Nearest_Neighbors, Gradient_Boosting, Decision_Tree, XGBoost, Random_Forest, and Neural_Net. To evaluate the accuracy of the mentioned models, three statistical indicators including Score, RMSE, and MAE were used. Based on the results of the first part, Yazd province has changed from mild wet to mild drought in terms of meteorological drought (the amount of rainfall according to SPI), and this condition can worsen due to climate change. The models used in ML showed that SPI-6 (score ave = 0.977), SPI-3 (score ave = 0.936), SPI-24 (score ave = 0.571), and SPI-12 (score ave = 0.413) indices had the highest accuracy, respectively. The models of Neural_Net (score ave = 0.964-RMSE ave = 0.020-MAE ave = 0.077) and Gradient_Boosting (score ave = 0.551-RMSE ave = 0.124-MAE ave = 0.248) had the highest and lowest accuracy in prediction of the SPI in all four-time scales. Based on the results of the second part, about the SWI, Random_Forest model (score = 0.929-RMSE = 0.052-MAE = 0.150) and model of Neural_Net (score = 0.755-RMSE = 0.235-MAE = 0.456) had the highest and lowest accuracy, respectively. Also, hydrological drought (reduction of the groundwater level) of the region has been much more severe, and according to the low correlation coefficient of average SPI and SWI (R2 = 0.14), we found that the uncontrolled pumping wells, as a main factor than a shortage of rainfall, have aggravated the hydrological drought, and this region is at risk of becoming a more arid region in the future.

Analytical chromatography approaches during the synthesis and conjugation of methoxypolyethylene glycol-succinimidyl butanoate (mPEG-SBA) to epoetin beta.

Conjugation of epoetin beta (EPO) with methoxypolyethylene glycol-succinimidyl butanoate (mPEG-SBA) was studied. The compound mPEG-SBA was synthesized from mPEG, and the obtained intermediates and final product were analyzed by a reversed-phase chromatographic system equipped with an evaporative light scattering detector. Labeling the hydroxyl group in PEGs with benzoyl chloride and succinimide with benzylamine was applied to resolve and characterize different PEGs. The synthesized mPEG-SBA was used for the PEGylation of EPO. A size-exclusion chromatographic method monitored the reaction, simultaneously determining the PEGylated and unreacted EPO and protein aggregates. A borate buffer (0.1 M, pH 7.8) and PEG/protein molar ratio of 3:1 produced a maximum amount of monoPEGylated EPO with the minimum amount of polyPEGylated EPO variants. Although EPO is considered a stable glycoprotein hormone that remains monomeric when refrigerated, PEGylation of EPO with mPEG-SBA resulted in the significant formation of EPO dimer. The formation of EPO dimer and polyPEGylated EPO was pH-dependent, showing higher amounts of aggregates and lower amounts of polyPEGylated forms in lower pH values. Accordingly, aggregated EPO should be considered a major PEGylation-related impurity. In conclusion, the present study highlighted the importance of having suitable analytical approaches in controlling mPEG-SBA synthesis and conjugation to EPO.