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Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Abstract An efficient finite difference approach is adopted to analyze the solution of a novel fractional-order mathematical model to control the co-circulation of double strains of dengue and COVID-19. The model is primarily built on a non-integer Caputo fractional derivative. The famous fixed-point theorem developed by Banach is employed to ensure that the solution of the formulated model exists and is ultimately unique. The model is examined for stability around the infection-free equilibrium point analysis, and it was observed that it is stable (asymptotically) when the maximum reproduction number is strictly below unity. Furthermore, global stability analysis of the disease-present equilibrium is conducted via the direct Lyapunov method. The non-standard finite difference (NSFD) approach is adopted to solve the formulated model. Furthermore, numerical experiments on the model reveal that the trajectories of the infected compartments converge to the disease-present equilibrium when the basic reproduction number ( $${\mathbb {R}}_0$$ R 0 ) is greater than one and disease-free equilibrium when the basic reproduction number is less than one respectively. This convergence is independent of the fractional orders and assumed initial conditions. The paper equally emphasized the outcome of altering the fractional orders, infection and recovery rates on the disease patterns. Similarly, we also remarked the importance of some key control measures to curtail the co-spread of double strains of dengue and COVID-19.

Background:. The use of sensory nerve transfers to the anesthetic cornea has transformed the treatment of neurotrophic keratopathy by restoring ocular surface sensation and activating dysfunctional epithelial repair mechanisms. However, despite numerous reports on surgical techniques, there is a scarcity of information on the interdisciplinary management, preoperative assessment, and surgical decision-making, which are equally critical to treatment success. Methods:. This Special Topic presents a standardized, interdisciplinary preoperative workup based on our 10-year experience with corneal neurotization in 32 eyes of patients with neurotrophic keratopathy. Results:. Our assessment includes a medical history review, ophthalmic evaluation, and systematic facial sensory donor nerve mapping for light touch and pain modalities. This approach enables evidence-based patient selection, optimal surgery timing, and suitable donor nerve identification, including backup options. Conclusions:. Based on a decade-long experience, this special topic highlights the importance of interdisciplinary collaboration and provides a practical roadmap for optimizing patient selection and surgical decision-making in patients undergoing corneal neurotization.

Sodium octanoate (Na-oct), a simple, naturally-abundant, cheap and low-toxic organic molecule has been investigated for its adsorption and inhibition properties against the CO2 corrosion of C1018 carbon steel in 3.5 % NaCl under static (0 rpm) and hydrodynamic conditions (1000 rpm). At open circuit potential (OCP) under static condition, a Langmuir-type adsorption of Na-oct modified the dielectric property of the steel-solution interface by lowering double layer capacitance and increasing resistance to charge transfer, based on electrochemical impedance spectroscopy (EIS) analysis. Under this condition, potentiodynamic polarization (PDP) analysis showed that Na-oct adsorbed more preferentially on anodic sites of steel surface and impacted ∼96 % inhibition efficiency. Hydrodynamic condition at 1000 rpm caused a Langmuir and Temkin adsorption mechanism and diminished the Na-oct efficiency to ∼86 %. FTIR characterization revealed that the inhibitor adsorption was enabled by its COO– functional group. Computational modeling, using DFT and MDS, confirmed the experimental findings.

PURPOSEAccess to radiotherapy (RT) is now one of the stark examples of global cancer inequities. More than 800,000 new cancer cases require potentially curative or palliative RT services in Africa, arguably

Abstract Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.

Tesla's Full Self-Driving Beta (FSD) program introduces technology that extends the operational design domain of standard Autopilot from highways to urban roads. This research conducted 103 in-depth semi-structured interviews with users of Tesla's FSD Beta and standard Autopilot to evaluate the impact on user behavior and perception. It was found that drivers became complacent over time with Autopilot engaged, failing to monitor the system, and engaging in safety-critical behaviors, such as hands-free driving, enabled by weights placed on the steering wheel, mind wandering, or sleeping behind the wheel. Drivers' movement of eyes, hands, and feet became more relaxed with experience with Autopilot engaged. FSD Beta required constant supervision as unfinished technology, which increased driver stress and mental and physical workload as drivers had to be constantly prepared for unsafe system behavior (doing the wrong thing at the worst time). The hands-on wheel check was not considered as being necessarily effective in driver monitoring and guaranteeing safe use. Drivers adapt to automation over time, engaging in potentially dangerous behaviors. Some behavior seems to be a knowing violation of intended use (e.g., weighting the steering wheel), and other behavior reflects a misunderstanding or lack of experience (e.g., using Autopilot on roads not designed for). As unfinished Beta technology, FSD Beta can introduce new forms of stress and can be inherently unsafe. We recommend future research to investigate to what extent these behavioral changes affect accident risk and can be alleviated through driver state monitoring and assistance.

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee (49871/9) on November 9, 2019.

Background: Chronic nerve compression is the most common indication for nerve surgery. However, the clinical diagnosis still relies on surrogate parameters since devices for direct nerve compression pressure measurement (DNCPM) are clinically unavailable yet.Objectives: To review previous approaches to DNCPM and evaluate presently available microsensor systems for their feasibility and reliability in preclinical nerve compression models.Methods: A scoping literature review was conducted in accordance with the PRISMA-ScR guidelines. A subsequent market research aimed at identifying commercially available sensor systems potentially suitable for DNCPM. Sensors were evaluated for feasibility and safety of perineural sensor positioning, tissue compatibility and measurement reliability in a synthetic nerve compression model and an ex-vivo chicken leg model.Results: A scoping literature review identified 197 potentially eligible studies of which 65 were included in the analysis. Previous approaches to DNCPM predominantly used pressure sensing catheters designed for fluid- or intra-compartmental pressure measurement. A market research identified two piezoresistive sensor systems (IntraSense, SMi, United States; Mikro-Cath, Millar, United States) as potentially suitable for intraoperative DNCPM. In both preclinical models, the detected compression pressure differed significantly between sensors and systems showed substantial measurement variability with a median percent coefficient of variation between 15.5% and 32%. Sensor position was accountable for up to 99.1% of the variance.Conclusion: Measurement variability caused by unreliable sensor positioning is a key limitation of presently available sensors when applied for nerve compression measurements. Redesigned systems with small, flat-shaped and longitudinally oriented sensors and dedicated introducers would facilitate sensor positioning and therefore may allow for reliable measurements.

The introduction of automated vehicles means that some or all operational control over these vehicles is diverted away from a human driver to a technological system. The concept of Meaningful Human Control (MHC) was derived to address control issues over automated systems, allowing a system to explicitly consider human intentions and reasons. Applying MHC to technological systems, such as automated driving is a real challenge, and the main focus of this article. An approach with mathematical elaboration has been developed that offers a first quantifiable operationalisation of MHC for the traffic domain and for use with automated vehicles. A major contribution lies in the taxonomification of control for MHC in the broader traffic environment, including consideration of the driver, the vehicle, the traffic environment, considering behaviour, moral standards and societal values, which are considered in a case study. The demonstration case shows the validity of the developed approach for an automated vehicle overtaking a cyclist on an urban street. This article is one of the first to operationalise MHC to such a level of detail and opens the door to further development of the concept for technological implementation.

Background: Modern surgery demands high-quality and reproducibility. Due to new working directives, resident duty hours have been restricted and evidence exists that pure on-the-job training provides insufficient exposure. We hypothesize that supplemental simulations in animal models provide a realistic training to augment clinical experiences. This study reviews surgical training models, their costs and survey results illustrating academic acceptance.Methods: Animal models were identified by literature research. Costs were analyzed from multiple German and Austrian training programs. A survey on their acceptance was conducted among faculty and medical students.Results: 915 articles were analyzed, thereof 91 studies described in-vivo animal training models, predominantly for laparoscopy (30%) and microsurgery (24%). Cost-analysis revealed single-training costs between 307€ and 5,861€ depending on model and discipline. Survey results illustrated that 69% of the participants had no experience, but 66% would attend training under experienced supervision. Perceived public acceptance was rated intermediate by medical staff and students (4.26; 1–low, 10 high).Conclusion: Training in animals is well-established and was rated worth attending in a majority of a representative cohort to acquire key surgical skills, in light of reduced clinical exposure. Animal models may therefore supplement the training of tomorrow's surgeons to overcome limited hands-on experience until virtual simulations can provide such educational tools.

BACKGROUND:Peripheral nerve injury in the upper extremity is linked to high socioeconomic burden, yet cost-analyses are rare and from small cohorts. The objective of this study was to determine the costs and long-term socioeconomic effects of peripheral nerve injuries in the upper extremity in Germany. METHODS:We analyzed data of 250 patients with 268 work-related upper extremity nerve injuries from acute treatment to long-term follow-up on rehabilitation, sick-leave and disability-pension. RESULTS:Patients were on average 39.9±14.2 years old, male (85%) and mean inpatient treatment was 7±6 days. Location of nerve was 8% (N = 19) proximal to the wrist, 26% (N = 65) at the wrist and metacarpus, and 66% (N = 166) at phalangeal level. Acute in-patient treatment for (single) median nerve injury accounted for 66% with hospital reimbursement of 3.570€, ulnar nerve injury for 24% and 2.650€ and radial nerve injury for 10% and 3.166€, all including finger nerve injuries. The remaining were combined nerve injuries, with significantly higher costs, especially if combined with tendon 5.086€ or vascular injury 4.886€. Based on location, nerve injuries proximal to the wrist averaged 5.360±6.429€, at the wrist and metacarpus 3.534±2.710€ and at the phalangeal level 3.418±3.330€. 16% required rehabilitation with average costs of 5.842€ and stay of 41±21 days. Sick leave was between 11-1109 days with an average of 147 days with socioeconomic costs of 197€/day, equaling on average 17.640€. 30% received a mean yearly disability pension of 3.187€, that would account to 102.167€ per lifetime. CONCLUSION:This large German patient sample indicates that nerve injury has a major impact on function and employment, resulting in significant health care costs. Both proximal and distal nerve injuries led to long-term disability, subsequent sick-leave and in 30% to permanent disability pension. These data are determined to support future studies and health economical work on prevention, treatment and rehabilitation of these often small injuries with great consequences.

The capacity drop forms a major reason why the prevention of congestion is targeted by traffic management, as lower capacities are detrimental to traffic throughput. Various reasons describing the dynamics behind the capacity have been described, however one of these, reaction times, has had less explicit attention when modelling on a macroscopic flow level. In this contribution, a method to include the effect of reaction times for the capacity drop in heterogeneous traffic is proposed. The applied method further overcomes difficulties in including reaction times in a discrete time model through relaxation of the updating process in the discretization. This approach is novel for application in the considered first order approach, which is practise ready, contrary to many other models that propose similar approaches. The combination of the introduced method and the model form a solid development and method to apply the capacity drop based on this causation of the capacity drop. The results of the experiment case showed that the influence of traffic heterogeneity had a limited effect on the severity of the capacity drop, while it did influence the time of congestion onset. The influence of the reaction time on traffic showed greater capacity drop values for greater reaction time settings. The findings showed the method effective and valid, while the model application is also practise ready. Keywords: Capacity drop, Traffic modelling, Heterogeneous traffic, Traffic flow

Nerve injury is often associated with limited axonal regeneration and thus leads to delayed or incomplete axonal reinnervation. As a consequence of slow nerve regeneration, target muscle function is often insufficient and leads to a lifelong burden. Recently, the diagnosis of nerve injuries has been improved and likewise surgical reconstruction has undergone significant developments. However, the problem of slow nerve regeneration has not been solved. In a recent meta-analysis, we have shown that the application of low-intensity ultrasound promotes nerve regeneration experimentally and thereby can improve functional outcomes. Here we want to demonstrate the experimental effect of low intensity ultrasound on nerve regeneration, the current state of investigations and its possible future clinical applications.

The slow axonal regeneration and consecutive delayed muscle reinnervation cause persistent functional deficits following peripheral nerve injury, even following sufficient surgical nerve reconstruction. Preclinically, adjunct ultrasound therapy has shown to significantly accelerate nerve regeneration and thereby improve muscle function compared to nerve reconstruction alone. However, although FDA-approved and clinically well-tested ultrasound devices for other conditions such as delayed-healing fractures are available, they have not been investigated for peripheral nerve injury yet. Aiming to provide a fast clinical translation, we evaluated EXOGEN (Bioventus LLC, Durham, USA), a clinical device for low-intensity ultrasound therapy in various treatment intervals following peripheral nerve surgery. Sixty rats, randomized to five groups of twelve animals each, underwent median nerve transection and primary epineural nerve reconstruction. Post-surgically the ultrasound therapy (duration: 2 min, frequency: 1.5 MHz, pulsed SATA-intensity: 30 mW/cm2, repetition-rate: 1.0 kHz, duty-cycle: 20%) was applied either weekly, 3 times a week or daily. A daily sham-therapy and a control-group served as references. Functional muscle testing, electrodiagnostics and histological analyses were used to evaluate nerve regeneration. The post-surgically absent grip strength recovered in all groups and increased from week four on without any significant differences among groups. The weekly treated animals showed significantly reduced target muscle atrophy compared to sham-treated animals (p = 0.042), however, with no significant differences to three-times-a-week-, daily treated and control animals. The number of myelinated axons distal to the lesion site increased significantly in all groups (p < 0.001) without significant difference among groups (p > 0.05). A full recovery of distal latency was achieved in all groups and muscle function and CMAP recurred with insignificant differences among groups. In conclusion, the clinically available FDA-approved ultrasound device did not promote the axonal regeneration following nerve injury in comparison to control and sham groups. This is in contrast to a conclusive preclinical evidence base and likely due to the insufficient ultrasound-intensity of 30 mW/cm2. We recommend the clinical investigation of 200–300 mW/cm2.

Weather conditions are widely acknowledged to contribute to the occurrence of congestion on motorway traffic by influencing both traffic supply and traffic demand. To the best of our knowledge, this is the first paper that explicitly integrates supply and demand effects in predicting the influence of adverse weather conditions on the probability of occurrence of congestion. Traffic demand is examined by conducting a stated adaptation experiment, in which changes in travel choices are observed under adverse weather scenarios. Based on these choices, a Panel Mixed Logit model is estimated. Supply effects are taken into account by examining the influence of precipitation on motorway capacity. Based on the Product Limit Method, capacity distribution functions are estimated for dry weather, light rain and heavy rain. With the developed model to integrate the supply and demand effects breakdown probabilities can be calculated for any given traffic demand and capacity. The results show that rainfall leads to a significant increase in the probability of traffic breakdown at bottleneck locations. Interestingly the probability of a breakdown at these bottleneck locations is predicted to be slightly higher in light rain (98.7%) than in heavy rain (95.7%) conditions, which is the result of the higher traffic demand in light rain conditions. Based on the results presented in this paper, it can be recommended to always incorporate both supply and demand effects in the predictions of motorway breakdown probabilities due to adverse weather conditions to improve the validity of the predictions.