Time-dependent Delivery Research Articles

THE TREATMENT, MANAGEMENT, DEMOGRAPHICS, AND ECONOMIC COSTS OF ORTHOPAEDIC INJURIES SUSTAINED IN MOTORCYCLE ACCIDENTS IN DELIVERY DRIVERS IN SOUTH AFRICA

Motorcycle accident-related traffic accidents contribute significantly to the burden of orthopaedic injuries seen in the South African Healthcare system. Subsequent to the Covid-19 pandemic, there has been an increase in the number of delivery drivers on the roads of South Africa. Many of these delivery drivers have no formal employment contracts. We aim to describe the demographics and injury patterns in motorcyclists involved in time dependent delivery work in South Africa; and to quantify the cost to the state of their orthopaedic surgeries.We performed a consecutive case series study at all of the hospitals draining the study region over the period of one year. Epidemiological, clinical and cost to hospital data was collected from medical records, digital radiographs, theatre invoices and a dedicated patient questionnaire.ProvisionalSo far 41 delivery drivers were captured by the study over a period of 11 months. All drivers were male and the vast majority foreign nationals. 11 patients were polytraumatised and 5 required admission to an intensive care unit. The most common injury patterns were closed femur fractures (17) followed by tibial shaft fractures (13). The average cost of surgery was R35 049 and average cost of ward stay R44 882 at an average of 10 days admission in a general ward. Overall, an estimated total of R 3.1 million rand was spent on these injuries.Informally employed “app users” performing delivery work on motorcycles in South Africa have added a significant burden to the cost of state healthcare since 2020. The vast majority of these patients are foreign nationals who do not hold South African licences or health insurance. They are sustaining high energy injuries typical of motorcycle-car accidents and many of them are left with lifelong loss of function.

Interplay Effect of Splenic Motion for Total Lymphoid Irradiation in Pediatric Proton Therapy.

(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized.

Solving the time dependent minimum tour duration and delivery man problems with dynamic discretization discovery

In this paper, we present exact methods for solving the Time Dependent Minimum Tour Duration Problem (TD-MTDP) and the Time Dependent Delivery Man Problem (TD-DMP). Both methods are based on a Dynamic Discretization Discovery (DDD) approach for solving the Time Dependent Traveling Salesman Problem with Time Windows (TD-TSPTW). Unlike the TD-TSPTW, these problems involve objective functions that depend in part on the time at which the vehicle departs the depot. As such, optimizing these problems adds a scheduling dimension to the problem. We present multiple enhancements to the DDD method, including enabling it to dynamically determine which waiting opportunities at the depot to model. With an extensive computational study we demonstrate that the resulting methods outperform all known methods for both the TD-MTDP and TD-DMP on instances taken from the literature.

Managing in real-time a vehicle routing plan with time-dependent travel times on a road network

Geographic information systems, global positioning systems, traffic flow sensors and cellular phones are sources of real-time traffic data in road networks. However, many vehicle routing algorithms do not account for this real-time information. In this paper, we consider the problem of adjusting in real-time a time-dependent delivery plan to respond to dynamic changes in travel times. We also consider a variant of the problem in which some customer requests can be canceled. The goal is to minimize disruption by maintaining as much as possible the current planned routes, although without compromising too much solution quality. Computational results obtained by solving instances with up to 500 customers are reported and compared with a strategy that maintains the planned routes, whatever the cost.

A Ligand‐Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery

Here we report the first use of ligand‐directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand‐directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for time‐dependent release of active drug following hydrolysis and self‐immolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co‐crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time‐dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work.

Travel speed prediction based on learning methods for home delivery

Abstract The travel time to proceed from one location to another in a network is an important consideration in many urban transportation settings ranging from the planning of delivery routes in freight transportation to the determination of shortest itineraries in advanced traveler information systems. Accordingly, accurate travel time predictions are of foremost importance. In an urban environment, vehicle speeds, and consequently travel times, can be highly variable due to congestion caused, for instance, by accidents or bad weather conditions. At another level, one also observes daily patterns (e.g., rush hours), weekly patterns (e.g., weekdays versus weekend), and seasonal patterns. Capturing these time-varying patterns when modeling travel speeds can provide an immediate benefit to commercial transportation companies that distribute goods, since it allows them to better optimize their routes and reduce their environmental footprint. This paper presents the first part of a project aimed at optimizing time-dependent delivery routes in an urban setting. It focuses on the prediction of travel speeds using as input GPS traces of commercial vehicles collected over a significant period of time. The proposed algorithmic framework is made of a number of macro-steps where different machine learning and data mining methods are applied. Computational results are reported on real data to empirically demonstrate the accuracy of the obtained predictions.

PGI20 MULTIMATRIX VERSUS TIME-DEPENDENT DELIVERY OF MESALAZINE FOR ULCERATIVE COLITIS THERAPY IN KAZAKHSTAN: A HEALTH ECONOMIC EVALUATION

Heavy costs associated with the treatment of unspecified ulcerative colitis necessitate the choice of drugs that provide the optimal treatment outcomes within the existing budget constraints. In this study, we compared the multimatrix (MMX) delivery type versus time-dependent delivery of mesalazine for treatment of unspecified ulcerative colitis in terms of their clinical and economic effectiveness. A review of clinical effectiveness was conducted using a sensitive search strategy. 5 high-quality trials identified and used to inform clinical effectiveness parameters in the model. The economic assessment involved the construction of a Markov model comparing the two delivery types over both a short-term (5 years) and a long-term horizon (30 years) using local treatment guidelines and costs, an additional budget impact analysis and a sensitivity analysis of model parameters. The exchange rate used is dated by June 2019 according to the current market rate in Kazakhstan. According to the model, MMX delivery of mesalazine as first-line therapy for unspecified ulcerative colitis was found to be the dominant therapy compared to time-dependent delivery, producing better outcomes at lower costs (additional 0.015 QALY) and averted costs of 193662 KZT (504.32 USD) per patient in the 5-year model, additional 0.038 QALY and averted costs of 1066659 KZT (2777.7 USD) per patient in the 30-year model). MMX mesalazine was associated with a longer remission stage and fewer relapses. The model was found to be sensitive to MMX mesalazine treatment response period, probability of progression to remission on MMX mesalazine and treatment-related costs. Using the MMX delivery of mesalazine in favor of time-dependent delivery for the treatment of unspecified ulcerative colitis appears to be a cost-effective option in the context of healthcare system of Kazakhstan, with potentially improved outcomes and considerable healthcare budget savings.

Sustainable performance of just-in-time (JIT) management in time-dependent batch delivery scheduling of precast construction

Abstract Despite a great deal of research into precast production scheduling published in academic journals worldwide, little attention has been given to environmental performance related to precast construction transportation and assembly scheduling problems. To address this issue, this paper studies the Just-in-Time (JIT) strategy for supply chain management of precast construction while considering time-dependent transportation time and on-site assembly time. There are two main contributions of our work. First, our analysis expands the current batch-scheduling model of minimizing earliness/tardiness penalties, by incorporating environmental impact considering the time-dependent transportation time and economic impact of resources wasted by waiting for on-site assembly. Second, we quantify the economic and environmental performance using our research objective, consisting of earliness/tardiness penalties, an additional transportation time penalty, and a resource waste penalty. The optimal results show that, compared with the supplier's intuitive minimax optimization with deliveries on the earliest due date, there is an average 10.7% reduction of the objective value of a one-day assembly task by our proposed method. The results also show that the objective of achieving additional environmental performance conflicts with that of obtaining economic performance. However, sensitivity analysis further shows it is not always true to consider only additional environmental performance for the suppliers to achieve ‘green’ value. For a sustainable business, the customer's service-JIT delivery should also be considered. Thus, when the policy makers assign importance weights to different objectives, they should fully consider both the economic and environmental impacts. The research contributes to batch delivery theory by expanding the approach to a time-dependent delivery model by considering both the economic and environmental effects. The method developed is of practical value for precast building projects to help in the successful implementation of sustainable development.

Recent Comparative Studies on the Performance and Survival Rate of African Catfish (Clarias gariepinus) Larval Produced under Natural and Synthetics Hormones: A Review

Induced breeding in African catfish (C. gariepinus) became germane in addressing unreliable seed supply due to low fertilization and egg hatchability, improper selection and use of natural or synthetic hormones to induce ovulation and spawning. The proper use of hormones promote reproduction in fish which is controlled by several factors such as sex steroids in the regulation of reproductive processes which are controlled through the brain-pituitary gonadal axis. A review was conducted on recent comparative studies on the performance and survival rate of African catfish (C. gariepinus) larval produced under natural and synthetics hormones. More than 20 journal published papers on inducing ovulation and spawning in African catfish (C. gariepinus) either by using natural or synthetic hormones, mostly from West Africa were reviewed. Literatures suggested that, using synthetic or non- synthetic hormones ensure availability of matured quality eggs, and ensuring good and viable milt production for commercial fish farming. Among reviewed papers revealed that, higher fertilization, hatching and survival rate of African catfish larval were achieved at 0.4-0.5 ml/kg of Ovaprim compared to Ovatide, Ovulin and Pituitary Gland Extract. In ovarian lavage with combination of sperm and hormone method, the simplicity of induced spawning can be combined, with a less time dependent delivery of sperm than with conventio na l, in-vitro fertilization. Therefore, this review suggests that African catfish seeds production can be encouraged through the use of Ovaprim. However, Catfish Pituitary Gland Extract (CPE) which is more readily available at farm level can also be used in-vitro fertilization in case there will be any shortage of Ovaprim whose supply varies with changes in import duties. In addition, to optimize fertilization and larval rearing pituitary gland extract in combination with disinfectants such as FA and MG can be used.

Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries.

The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., "movie" mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID's angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, less EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into "frame-averaged" EPID images using matlab. Each frame-averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a ±1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac's average gantry speed and the dose per fraction. The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region's mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment's dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors' clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors' required level of accuracy in the dose reconstruction.

Self-assembly of amphiphilic Janus dendrimers into uniform onion-like dendrimersomes with predictable size and number of bilayers.

A constitutional isomeric library synthesized by a modular approach has been used to discover six amphiphilic Janus dendrimer primary structures, which self-assemble into uniform onion-like vesicles with predictable dimensions and number of internal bilayers. These vesicles, denoted onion-like dendrimersomes, are assembled by simple injection of a solution of Janus dendrimer in a water-miscible solvent into water or buffer. These dendrimersomes provide mimics of double-bilayer and multibilayer biological membranes with dimensions and number of bilayers predicted by the Janus compound concentration in water. The simple injection method of preparation is accessible without any special equipment, generating uniform vesicles, and thus provides a promising tool for fundamental studies as well as technological applications in nanomedicine and other fields.

Injection-Molded Capsular Device for Oral Pulsatile Release: Development of a Novel Mold

The development of a purposely devised mold and a newly set up injection molding (IM) manufacturing process was undertaken to prepare swellable/erodible hydroxypropyl cellulose-based capsular containers. When orally administered, such devices would be intended to achieve pulsatile and/or colonic time-dependent delivery of drugs. An in-depth evaluation of thermal, rheological, and mechanical characteristics of melt formulations/molded items made of the selected polymer (Klucel® LF) with increasing amounts of plasticizer (polyethylene glycol 1500, 5%-15% by weight) was preliminarily carried out. On the basis of the results obtained, a new mold was designed that allowed, through an automatic manufacturing cycle of 5 s duration, matching cap and body items to be prepared. These were subsequently filled and coupled to give a closed device of constant 600 μm thickness. As compared with previous IM systems having the same composition, such capsules showed improved closure mechanism, technological properties, especially in terms of reproducibility of the shell thickness, and release performance. Moreover, the ability of the capsular container to impart a constant lag phase before the liberation of the contents was demonstrated irrespective of the conveyed formulation.

WE‐C‐BRB‐11: Four Dimensional Analysis of VMAT Delivery

Purpose: To develop a technique for analyzing the time dependent delivery of VMAT treatment with a 4D diode array. Method and Materials: VMAT treatment plans with two full arcs for H&amp;N patients were generated with Pinnacle SmartArc. The plan was delivered and measured with a 4D diode array (ArcCHECK). ArcCHECK records data every 50 milliseconds and saves in a movie file for post analysis. Algorithm was designed to derive gantry angle for each signal update based on the intersection of beam edges with the cylindrical ArcCHECK phantom. Angular correction factor for each diode was interpolated and applied, with intrinsic sensitivity correction factor, to the raw data to remove diode response dependence. Based on the derived gantry angles, dose between any two control points can be integrated and written into an ArcCHECK measurement file. Measured dose distribution at any instance or integrated between any two control points can be compared with the Pinnacle calculated control point dose using the MapCHECK software. Results: Five IMRT beams were used to test the accuracy of the gantry angle derivation algorithm. The maximum mean error was 0.6o. For VMAT delivery, the derived gantry angles showed a smooth 360o clockwise gantry motion starting from 180o. Seven individual control points (#1, #15, #1∼3, #1∼5, #4∼5, #5∼15 and #1∼90) were selected for dose comparison in relative dose mode. The average passing rates with 3%/3mm and 2%/2mm were 97.1% and 90.5%, respectively. Conclusion: Control point based dose comparison showed satisfactory results indicating the accurate delivery of VMAT plans. The technique will be valuable in diagnosing VMAT delivery system errors, especially those originating from MLC and gantry motion.

Feasibility, stability and release performance of a time-dependent insulin delivery system intended for oral colon release

The aim of the present work was to evaluate the viability of a time-dependent delivery platform (Chronotopic TM) in preparing an insulin-based system intended for oral colon delivery. The main objectives were to assess the influence of the manufacturing process and storage conditions on the protein stability. Insulin-loaded cores were manufactured by direct compression and were subsequently coated with hydroxypropyl methylcellulose (HPMC) in a top-spray fluid bed up to increasing weight gains, namely 20%, 60% and 100%. In order to evaluate the impact the operating conditions may have on the protein integrity, insulin and its main degradation products ( A21-desamido insulin – A21, Other Insulin-Related Compounds – OIRCs, and High-Molecular Weight Proteins – HMWPs) were assayed on samples collected after each process step by chromatographic methods. Furthermore, long-term (4 °C) and accelerated (25 °C–60% RH) stability studies were carried out on tablet cores and coated systems by assessing insulin, A21, OIRC and HMWP percentages throughout a one-year storage period. In addition, the in vitro release behaviour was investigated during the same study period. The overall results indicated that the manufacturing process is not detrimental for insulin integrity and that 4 °C storage temperature alters neither the protein content nor the release performances of the device. It was therefore concluded that insulin-containing systems intended for oral colon delivery can be obtained by the Chronotopic TM technology.

Time-controlled oral delivery systems for colon targeting

In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.

A microfluidic chip for heterogeneous immunoassay using electrokinetical control

This article presents the development of a novel, automated, electrokinetically controlled heterogeneous immunoassay on a poly(dimethylsiloxane) (PDMS) microfluidic chip. A numerical method has been developed to simulate the electrokinetically driven, time-dependent delivery processes of reagents and washing solutions within the complex microchannel network. Based on the parameters determined from the numerical simulations, fully automated on-chip experiments to detect Helicobacter pylori were accomplished by sequentially changing the applied electric fields. Shortened assay time and much less reagent consumptions are achieved by using this microchannel chip while the detection limit is comparable to the conventional assay. There is a good agreement between the experimental result and numerical prediction, demonstrating the effectiveness of using CFD to assist the experimental studies of microfluidic immunoassay.

Polymer Colon Drug Delivery Systems and their Application to Peptides, Proteins, and Nucleic Acids

Most therapeutic peptides and proteins are administered via the parenteral route, which presents numerous drawbacks and limitations. To overcome these drawbacks, alternative administration routes, such as oral or mucosal routes, have been investigated. The oral route presents a series of attractive advantages for the administration of therapeutic compounds, such as the avoidance of the pain and discomfort associated with injections, good patient compliance, and being less expensive to produce. However, oral administration of peptides, proteins, or nucleic acids also presents several difficulties because of their instability in the upper gastrointestinal (GI) tract and their poor transport across biologic membranes. Among the various approaches developed to improve the oral delivery of peptides, proteins, or nucleic acids, specific delivery to the colon has attracted a lot of interest because of its potential for the local treatment of colonic diseases, systemic delivery of poorly absorbed drugs, and vaccine delivery. Numerous pharmaceutical approaches described in this review have been exploited for the development of colon-targeted drug delivery systems using various concepts, such as pH-dependent, time-dependent, pressure-controlled, or bacterially triggered delivery systems. The action of the pH-dependent delivery systems is based on pH differences between the stomach and the ileum. Time-dependent delivery systems are based on the transit time of pharmaceutical dosage forms in the GI tract, drug release being delayed until they reach the colon. A combination of pH- and time-dependent delivery systems has also been described to avoid the drawbacks of both strategies. The pressure-controlled delivery concept exploits the physiologic luminal pressure of the colon as the driving force for site-specific delivery of drugs. Finally, bacterially triggered delivery systems exploit the enormous diversity of enzymatic activity associated with the colonic microflora. Bacterially triggered delivery systems are generally composed of polymers, which are specifically degraded by colonic enzymes of microbial origin. These polymers have been used to form prodrugs with the drug moiety, as coating materials for the drug core, or as embedding media to entrap the drug into matrix or hydrogel systems. Each of these concepts has advantages and limitations. They present varied colonic specificity and, among them, bacterially triggered delivery systems in particular show the greatest potential for colonic delivery of peptides, proteins, and nucleic acids.

A Novel pH- and Time-Dependent System for Colonic Drug Delivery

A novel pH- and time-dependent delivery system was developed for delivering drugs to the colon. In vitro studies showed that this novel system could release the drug at a predetermined time, which was mainly controlled by the coating layers of the system. The delayed time of the press-coating layer was controlled by its erosion rate, which followed Hixson-Crowell equation. A proper selection of such factors as the viscosity grade of HPMC and tablet hardness, etc., can help reproduce the drug release profile as expected. The transit profiles in two healthy volunteers by gamma scintigraphy demonstrated that the tablets were able to pass through the stomach and small intestine intact and could safely reach the distal end of the small intestine, where the system began to release the drug contained in the core tablet. For both of the volunteers, disintegration of the tablets occurred in the ascending colon, which had highlighted the potential of this system for colonic drug delivery.

Encapsulation of Ibuprofen in Mesoporous Silica: Solid State NMR Characterization

AbstractMesoporous silica materials have been studied for the time-dependent delivery of bioactive agents. It has already been shown that ibuprofen molecules can be encapsulated with loading as high as 30 wt% in MCM-41 silica, functionalized or not by amino groups. Interactions between the guest molecules and the host matrix have been investigated by 1H, 29Si and 13C solid state NMR spectroscopy. These experiments demonstrate an extremely high mobility of the ibuprofen molecules when the matrix is not functionalized, despite of the presence of a carboxylic function on the ibuprofen molecules. On the contrary, when the silica matrix is functionalized by amino groups, the 13C NMR response shows a strong restriction in mobility suggesting the existence of interactions between the amino groups and the carboxylic groups.