A Systematic Review of Pharmacovigilance Systems in Developing Countries Using the WHO Pharmacovigilance Indicators.

BACKGROUND: In the context of the growth of pharmacovigilance (PV) among developing countries, this systematic review aims to synthesise current research evaluating developing countries' PV systems' performance. METHODS: EMBASE, MEDLINE, CINAHL Plus and Web of Science were searched for peer-reviewed studies published in English between 2012 and 2021. Reference lists of included studies were screened. Included studies were quality assessed using Hawker et al.'s nine-item checklist; data were extracted using the WHO PV indicators checklist. Scores were assigned to each group of indicators and used to compare countries' PV performance. RESULTS: Twenty-one unique studies from 51 countries were included. Of a total possible quality score of 36, most studies were rated medium (n = 7 studies) or high (n = 14 studies). Studies obtained an average score of 17.2 out of a possible 63 of the WHO PV indicators. PV system performance in all 51 countries was low (14.86/63; range: 0-26). Higher average scores were obtained in the 'Core' (9.27/27) compared to 'Complementary' (5.59/36) indicators. Overall performance for 'Process' and 'Outcome' indicators was lower than that of 'Structural'. CONCLUSION: This first systematic review of studies evaluating PV performance in developing countries provides an in-depth understanding of factors affecting PV system performance.

Nitric oxide biosensor uncovers diminished ferrous iron-dependency of cultured cells adapted to physiological oxygen levels.

Iron is an essential metal for cellular metabolism and signaling, but it has adverse effects in excess. The physiological consequences of iron deficiency are well established, yet the relationship between iron supplementation and pericellular oxygen levels in cultured cells and their downstream effects on metalloproteins has been less explored. This study exploits the metalloprotein geNOps in cultured HEK293T epithelial and EA.hy926 endothelial cells to test the iron-dependency in cells adapted to standard room air (18 kPa O2) or physiological normoxia (5 kPa O2). We show that cells in culture require iron supplementation to activate the metalloprotein geNOps and demonstrate for the first time that cells adapted to physiological normoxia require significantly lower iron compared to cells adapted to hyperoxia. This study establishes an essential role for recapitulating oxygen levels in vivo and uncovers a previously unrecognized requirement for ferrous iron supplementation under standard cell culture conditions to achieve geNOps functionality.

Complexities of the chemogenetic toolkit: Differential mDAAO activation by d-amino substrates and subcellular targeting.

A common approach to investigate oxidant-regulated intracellular pathways is to add exogenous H2O2 to living cells or tissues. However, the addition of H2O2 to the culture medium of cells or tissues approach does not accurately replicate intracellular redox-mediated cell responses. d-amino acid oxidase (DAAO)-based chemogenetic tools represent informative methodological advances that permit the generation of H2O2 on demand with a high spatiotemporal resolution by providing or withdrawing the DAAO substrate d-amino acids. Much has been learned about the intracellular transport of H2O2 through studies using DAAO, yet these valuable tools remain incompletely characterized in many cultured cells. In this study, we describe and characterize in detail the features of a new modified variant of DAAO (termed mDAAO) with improved catalytic activities. We tested mDAAO functionality in several cultured cell lines employing live-cell imaging techniques. Our imaging experiments show that mDAAO is suitable for the generation of H2O2 under hypoxic conditions imaged with the novel ultrasensitive H2O2 sensor (HyPer7). Moreover, this approach was suitable for generating H2O2 in a reversible and concentration-dependent manner in subcellular locales. Furthermore, we show that the choice of d-amino acids differentially affects mDAAO-dependent intracellular H2O2 generation. When paired with the hydrogen sulfide (H2S) sensor hsGFP, administration of the sulfur-containing amino acid d-cysteine to cells expressing mDAAO generates robust H2S signals. We also show that chemogenetic H2O2 generation in different cell types yields distinct HyPer7 profiles. These studies fully characterize the new mDAAO as a novel chemogenetic tool and provide multiparametric approaches for cell manipulation that may open new lines of investigations for redox biochemists to dissect the role of ROS signaling pathways with high spatial and temporal precision.

A qualitative exploration of pharmacovigilance policy implementation in Jordan, Oman, and Kuwait using Matland's ambiguity-conflict model.

BACKGROUND: As Arab countries seek to implement the 'Guideline on Good Pharmacovigilance Practice (GVP) for Arab countries', understanding policy implementation mechanisms and the factors impacting it can inform best implementation practice. This study aimed to explore the mechanisms of and factors influencing pharmacovigilance policy implementation in Arab countries with more established pharmacovigilance systems (Jordan, Oman), to inform policy implementation in a country with a nascent pharmacovigilance system (Kuwait). RESULTS: Matland's ambiguity-conflict model served to frame data analysis from 56 face-to-face interviews, which showed that policy ambiguity and conflict were low in Jordan and Oman, suggesting an "administrative implementation" pathway. In Kuwait, policy ambiguity was high while sentiments about policy conflict were varied, suggesting a mixture between "experimental implementation" and "symbolic implementation". Factors reducing policy ambiguity in Jordan and Oman included: decision-makers' guidance to implementors, stakeholder involvement in the policy's development and implementation, training of policy implementors throughout the implementation process, clearly outlined policy goals and means, and presence of a strategic implementation plan with appropriate timelines as well as a monitoring mechanism. In contrast, policy ambiguity in Kuwait stemmed from the absence or lack of attention to these factors. Factors reducing policy conflict included: the policy's compliance with internationally recognised standards and the policy's fit with local capabilities (all three countries), decision-makers' cooperation with and support of the national centre as well as stakeholders' agreement on policy goals and means (Jordan and Oman) and adopting a stepwise approach to implementation (Jordan). CONCLUSIONS: Using Matland's model, both the mechanism of and factors impacting successful pharmacovigilance policy implementation were identified. This informed recommendations for best implementation practice in Arab as well as other countries with nascent pharmacovigilance systems, including increased managerial engagement and support, greater stakeholder involvement in policy development and implementation, and undertaking more detailed implementation planning.

Image processing for detecting complete two dimensional properties' distribution of granules produced in twin screw granulation.

In this study, an image processing technique is implemented to measure complete two-dimensional particle size and liquid content distribution (2D-distribution) of the granules produced in twin screw granulation (TSG). The effects of liquid binder viscosity and liquid to solid ratio (L/S) on the 2D-distribution, and the residence time distribution were studied. The effect of screw configuration on granule formation at different conditions was also investigated, were the mean residence time distribution (MRTD) in conveying elements decreases with the increase of L/S ratio and viscosity. While in kneading elements the MRTD decreases with the increase of L/S and increases with the increase of viscosity. The mean liquid saturation level of the granule is exponentially related to its size. As well, the increase in binder viscosity and L/S ratio leads to more uneven/bi-model particle size distribution (PSD) in the conveying elements, while kneading elements change the initial bi-model PSDs into more homogenous mono-model like distributions.

Complete two dimensional population balance modelling of wet granulation in twin screw.

In this study, a complete two dimensional (internal coordinates) population balance model (2D-PBM) is developed, calibrated and validated as a predictive tool for predicting the particle size and the liquid content distribution of the granules produced from twin screw granulation (TSG). The model is calibrated and validated using experimental distributions for the two internal coordinates that are captured using image processing. Granulation runs are conducted at multiple liquid to solid (L/S) ratios and liquid binder viscosities, and then used to calibrate and validate the 2D-PBM. The mathematical model accounts for aggregation and breakage of the particles occurring in three zones of the TSG with inhomogeneous screw configurations (2 conveying zones and 1 kneading zone). A Madec aggregation kernel, and a linear breakage selection function are used in the 2D-PBM and finite volume numerical approximation is used for solving the model. The calibrated model shows that the aggregation rate in the conveying elements is higher than in the kneading elements while the breakage rate in the kneading elements is much higher than in the conveying elements. Also, the increase in L/S ratio and liquid viscosity leads to higher aggregation rates and lower breakage rates.

Task-based mirror therapy enhances the upper limb motor function in subacute stroke patients: a randomized control trial.

BACKGROUND: The improvement of the upper limb disability, which is mainly caused by stroke, is still one of the rehabilitation treatment challenges. However, the effectiveness of task-based mirror therapy (TBMT) on subacute stroke with moderate and severe upper limb impairment has not been deeply explored. AIM: The purpose of this study was to investigate the effects of TBMT, in comparison to occupational therapy, in moderate and severe upper limb impairment by analyzing the motor function and activities of daily living in subacute stroke patients. DESIGN: A randomized controlled trial. SETTING: Rehabilitative inpatient unit. POPULATION: Thirty patients with moderate and severe-subacute stroke recruited from the Second Affiliated Hospital of Chongqing Medical University have been randomly divided into two groups; the task-based mirror therapy group (N.=15) and the control group (N.=15). METHODS: The first group received TBMT while the control group only underwent only occupational therapy without a mirror utilization. Taking into consideration that both groups received conventional therapy. The intervention time was equal for both groups consisting of 25 minutes per day for 25 days. Fugl-Meyer Assessment (FMA), Brunnstrom Assessment (BRS), Modified Barthel Index (MBI), and Modified Ashworth Scale (MAS) were used to assess the outcomes for this study. RESULTS: After 25 sessions of treatment, the patients in both groups have shown-improvement in the activates of daily living, motor recovery, and motor function. No significant differences between the two groups were observed on BRS and MBI. However, interestingly, the results of the TBMT group were significantly better than the control group in FMA (P<0.05) and certain aspects of MAS (elbow flexion, wrist flexion, wrist extension, and fingers extension with P<0.05). CONCLUSIONS: This study shows that the combination of conventional rehabilitation treatment and TBMT is an effective way to improve the functional recovery in the upper limb stroke patients. CLINICAL REHABILITATION IMPACT: TBMT is a therapeutic technique that can be used in subacute stroke patients with moderate and severe upper limb impairment.

Compartmental approach for modelling twin-screw granulation using population balances.

In this study, a compartmental population balance model (CPBM) is developed as a predictive tool of particle size distribution (PSD) for wet granulation in co-rotating twin-screw granulator (TSG). This model is derived in terms of liquid to solid ratio (L/S) and screw speed representing the main process parameters of the TSG. The mathematical model accounts for aggregation and breakage of the particles occurring in five compartments of the TSG with inhomogeneous screw configurations (3 conveying zones and 2 kneading zones). Kapur's aggregation kernel is implemented in granulation and finite volume numerical method is adapted for solving the mathematical model. The results show a dramatic improvement in solution accuracy compared to the cell average numerical method. Moreover, Kriging interpolation is used to interpolate for new values of empirical parameters at different L/S and screw speeds. Finally, the CPBM model is calibrated and validated using the experimental data.

Mass-based finite volume scheme for aggregation, growth and nucleation population balance equation.

In this paper, a new mass-based numerical method is developed using the notion of Forestier-Coste & Mancini (Forestier-Coste & Mancini 2012, SIAM J. Sci. Comput. 34, B840-B860. (doi:10.1137/110847998)) for solving a one-dimensional aggregation population balance equation. The existing scheme requires a large number of grids to predict both moments and number density function accurately, making it computationally very expensive. Therefore, a mass-based finite volume is developed which leads to the accurate prediction of different integral properties of number distribution functions using fewer grids. The new mass-based and existing finite volume schemes are extended to solve simultaneous aggregation-growth and aggregation-nucleation problems. To check the accuracy and efficiency, the mass-based formulation is compared with the existing method for two kinds of benchmark kernels, namely analytically solvable and practical oriented kernels. The comparison reveals that the mass-based method computes both number distribution functions and moments more accurately and efficiently than the existing method.

Multi-dimensional population balance modelling of pharmaceutical formulations for continuous twin-screw wet granulation: Determination of liquid distribution.

Two-dimensional population balance model (PBM) is developed in order to model pharmaceutical granules formation in a twin-screw wet granulator. Granule size and liquid content are considered as internal coordinates, while axial length of granulator is considered as external coordinate. Two types of initial liquid distribution are considered for the model development, i.e. constant and linear distributions. The main focus is on modeling and validation of liquid content distribution of granules. Regime-separated approach was used in order to capture the non-homogeneity of the granulator. The plug flow regime is considered for the conveying zone, while well-mixed regime is assumed for the kneading zone of twin-screw granulator. Aggregation and breakage are considered as the main mechanisms for granule formation and size control. Cell average method is used for solution of the PBM based on lumped parameter approach. In order to determine experimentally the distribution of liquid, liquid binder by dye addition was used in the process. The model findings are calibrated and validated by comparing with measured liquid content in each size fraction. The measured data is collected on a 12 mm twin-screw wet granulator using microcrystalline cellulose (MCC) and water soluble dye plus water as binder. The model indicated to be valid for MCC and needs to be validated with further excipients. The results revealed that increasing screw speed led to more uniform liquid distribution. Finally, the model findings indicated that 2D PBM is capable of predicting liquid distribution, and can be used as predictive tool in pharmaceutical continuous granulation.

ANN-Kriging hybrid model for predicting carbon and inorganic phosphorus recovery in hydrothermal carbonization.

Modeling of hydrothermal carbonization (HTC) of poultry litter to high-value materials was conducted in order to understand the process and predict the influence of process parameters on product properties. Reaction temperature and time were considered as inputs, whereas carbon and inorganic phosphorous recovery were considered as responses in the model. Artificial neural network (ANN) model was used in order to correlate the process parameters to the outputs. The model was trained and validated using the data collected from HTC experiments carried out at temperatures between 150 ≤ T ≤ 300 °C, and residence time between 30 ≤ t ≤ 480 min. In order to improve the predictability of ANN, more theoretical data points were generated using Kriging approach based on the available measured data. Kriging interpolation improved the ANN model dramatically in training and validation phases, where the carbon recovery model fitting was improved by 0.94% and 9.2% in training and validation respectively, and the inorganic phosphorous (IP) recovery model fitting was improved by a staggering 16.4% and 19.6% in training and validation respectively. This improvement is also reflecting on the derived profiles of carbon and IP recovery in terms of the process parameters. The validated model was then used to understand the effect of process parameters on the response. It was revealed that temperature has more significant effect on the carbon and phosphorous recovery, while the effect of reaction time is more important at low reaction temperatures. The derived profiles shows a monotonic increase in IP recovery and a monotonic decrease in Carbon recovery at higher temperatures and time, this is due to multiple mechanism occurring simultaneously in the HTC reactor at various temperatures and times.

Pyrolysis of waste tires: A modeling and parameter estimation study using Aspen Plus®.

This paper presents a simulation flowsheet model of a waste tire pyrolysis process with feed capacity of 150kg/h. A kinetic rate-based reaction model is formulated in a form implementable in the simulation package Aspen Plus, giving the flowsheet model the capability to predict more than 110 tire pyrolysis products as reported in experiments by Laresgoiti et al. (2004) and Williams (2013) for the oil and gas products respectively. The simulation model is successfully validated in two stages: firstly against experimental data from Olazar et al. (2008) by comparing the mass fractions for the oil products (gas, liquids (non-aromatics), aromatics, and tar) at temperatures of 425, 500, 550 and 610°C, and secondly against experimental results of main hydrocarbon products (C7 to C15) obtained by Laresgoiti et al. (2004) at temperatures of 400, 500, 600, and 700°C. The model was then used to analyze the effect of pyrolysis process temperature and showed that increased temperatures led to chain fractions from C10 and higher to decrease while smaller chains increased; this is attributed to the extensive cracking of the larger hydrocarbon chains at higher temperatures. The utility of the flowsheet model was highlighted through an energy analysis that targeted power efficiency of the process determined through production profiles of gasoline and diesel at various temperatures. This shows, through the summation of the net power gain from the plant for gasoline plus diesel that the maximum net power lies at the lower temperatures corresponding to minimum production of gasoline and maximum production of diesel. This simulation model can thus serve as a robust tool to respond to market conditions that dictate fuel demand and prices while at the same time identifying optimum process conditions (e.g. temperature) driven by process economics.

Evaluation of patient effective doses in CT urography, intravenous urography and renal scintigraphy.

Imaging of the renal system is performed with different techniques depending mainly on clinical symptoms and signs. This study intended to evaluate patient effective doses undergoing renal scintigraphy (technetium-99m-diethylene-triamine-pentaacetic acid), computed tomography urography (CTU) and intravenous urography (IVU). A total of 60 patients were evaluated using Orbiter 37 Gamma camera single head, dual-slice CT scanner and conventional X-ray machine with computed radiography (CR) processing unit. Patients effective dose were estimated using the administered activity, DosCal software and dose length product value for renal scan, IVU and CTU procedures, respectively. Patients' effective doses during renal scan, CTU and IVU procedures were 0.78 ± 0.18, 2.53 ± 0.94 and 1.81 ± 0.20 mSv, in that order. Patients were exposed to a higher effective dose during CTU compared with other two procedures. Patient doses depend on the size of patient, the type of scanner and the imaging protocol used. Effective doses considered low compared with previous studies.

The significance of cystic duct stones encountered during laparoscopic cholecystectomy.

BACKGROUND: Cystic duct stones (CDS) are occasionally encountered during laparoscopic cholecystectomy (LC). They may be noticed during the dissection of the cystic pedicle or seen to extrude from the cystic duct (CD) when it is divided or opened to perform the intraoperative cholangiogram (IOC). The procedures for dealing with CDS range from the simple removal of stones that fall out when the duct is opened to incising the duct over an impacted stone to facilitate its removal or converting to open surgery due to a large stone in a CD adherent to the bile duct (e.g., Mirizzi syndrome). Therefore, we set out to establish criteria that might be predictive of CDS, to examine the technical problems caused by them, to look for the most effective ways of avoiding adverse consequences, especially the risk of missing bile duct stones. METHODS: We performed a review and analysis of a database that included preoperative, operative, and postoperative data for all patients treated at our hospital who were found to have CDS. RESULTS: In a series of 520 LC performed over a period of 5 years, 64 cases of CDS were documented (12.3%). The preoperative risk factors in 45 of these cases (70.3%) were recent sever acute pain with or without liver function test (LFT) derangement (34.3%), jaundice (14%), pancreatitis (14%), and previous acute cholecystitis (7.8%). At operation, a single stone was found in the CD in 64% of the cases; multiple stones were found in 36%. Dissection of the pedicle was difficult in 21 cases and had to be carried out fundus-first in four cases. The CD was reported to be wide in 18 cases; five of them eventually needed to be closed with endoloops. Operative difficulty was reported in three of 19 cases where there were no preoperative risk factors. Simple removal of the stones was possible in most cases. CDS needed be crushed, the CD incised, or the procedure converted to open in only five cases (7.8%). IOC was attempted in all cases; it was normal in 39 (61%) and failed in two cases (3%). Eighteen patients (28%) were found to have bile duct stones; another five (7.8%) had CBD dilation or debris indicating possible recent passage of stones. Fourteen transcystic and nine direct bile duct explorations were performed. CONCLUSION: Some CDS may slip from the gallbladder into the CD or the CBD during dissection. Careful retraction and manipulation should therefore be done to minimize this risk. Most CDS are easy to deal with, but some of them can result in increased operative difficulty. If IOC is not carried out on a routine basis, it becomes mandatory if CDS are encountered because 35% of them may be associated with bile duct stones.

Poisoning from henna dye and para-phenylenediamine mixtures in children in Khartoum.

Poisoning by a mixture of henna dye and para-phenylenediamine dyes led to the hospitalization of 31 Sudanese children between 1984 and 1989. There was a characteristic clinical presentation. All children presented with an acute and severe angioneurotic oedema and 15 of the cases required emergency tracheostomy for respiratory obstruction. Acute renal failure occurred in five children who recovered after peritoneal dialysis. Mortality was high, all 13 deaths occurring within 24 hours of presentation. Hypotensive shock gave a poor prognosis. It is possible that similar cases may be occurring unrecognized where henna is traditionally used. A programme of public education and restriction of para-phenylenediamine is urgently required in The Sudan and other affected nations. Ingestion was accidental in 12 children, deliberate in 10 and homicidal in three cases. Cutaneous absorption was likely in the remaining six.