Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.

Apple (Malus × domestica Borkh.) production and quality in response to anti-hail nets.

Anti-hail nets are the best way to mitigate the effects of hailstorms in the orchards. Apple trees covered with nets may exhibit a variety of vegetative and reproductive responses, inclusive of changes in tree vigour, cropping, sugar contents, and fruit colour. The present study was conducted to assess the effect of timing of installation and colour of anti-hail net on cropping and fruit quality in high-density apple orchard for two consecutive seasons (2021 and 2022). White and blue colour nets of size (9 m × 30 m) 80 GSM (square mesh with non-sliding threaded, leno weave, and < 30% shading factor) were installed at three different time intervals (15 days before estimated full bloom, at full bloom, and 15 days after full bloom) on apple cultivar 'Jeromine'. The installation at different time and colour of anti-hail nets significantly exhibit variability in cropping, fruit quality, and bio-chemical metrics. The significant highest cropping (fruit yield, productivity, and yield efficiency) and fruit biochemical parameters (total soluble solids) were recorded in T3C2 (15 days after full bloom + white colour anti-hail net) followed by T2C2 (installed at full bloom + white colour anti-hail net). Hence, white colour anti-hail nets installed 15 days after full bloom increased fruit production and improved quality in comparison to blue colour anti-hail net in apple under high-density plantations.

Microbial pigments: Sources, current status, future challenges in cosmetics and therapeutic applications.

Color serves as the initial attraction and offers a pleasing aspect. While synthetic colorants have been popular for many years, their adverse environmental and health effects cannot be overlooked. This necessitates the search for natural colorants, especially microbial colorants, which have proven and more effective. Pigment-producing microorganisms offer substantial benefits. Natural colors improve product marketability and bestow additional benefits, including antioxidant, antiaging, anticancer, antiviral, antimicrobial, and antitumor properties. This review covers the various types of microbial pigments, the methods to enhance their production, and their cosmetic and therapeutic applications. We also address the challenges faced during the commercial production of microbial pigments and propose potential solutions.

Flap Closure in Neonatal Neural Tube Defects: Challenges in Flap Design and Lessons Learnt.

Background: Management of neural tube defects (NTDs) is challenging and the outcome is demanding. Aims: To analyze the outcomes in operated cases of NTDs closed using various types of flaps. Materials and Methods: The data between June 2017 and May 2023 were analyzed. The mode of presentation, timing of intervention, type of flap, neurological status after closure, status of the wound, presence of hydrocephalous, flap blackening, flap necrosis, features of sepsis, and the outcome were recorded and analyzed. Covered NTD; closure done using primary closure or 'Z' Plasty (everywhere); incomplete data; lost to follow-up; and not giving consent were excluded from the study. Results: Out of 92 cases, 35 were operated using the rhomboid flap, 33 using dufourmentel modification of limberg flap, and 24 using keystone island flap. The mean age at presentation was 4 days (range: 0-28 days). The mean duration of surgery after presentation was 2 days (range: 1-3 days). Mean operating time was 1.15 h (range: 0.45-3.15 h). A ventriculoperitoneal shunt was required in 62 cases at various stages. The preoperative and the postoperative power were nearly the same in all. Wound infection was seen in 2, 3, and 1 cases in each group. Blackening of the flap was seen in 3, 2, and 1 cases in three groups. Cerebrospinal fluid (CSF) leak was seen in 2, 2, and 0 cases. Wound dehiscence was present in one case in each group and sepsis was present in 2, 3, and 2, respectively. Conclusion: The management of open NTD requires adequate planning. CSF shunting and flap closure are often required.

Deciphering the melatonin-mediated response and signalling in the regulation of heavy metal stress in plants.

MAIN CONCLUSION: Melatonin has a protective effect against heavy metal stress in plants by immobilizing HM in cell walls and sequestering them in root cell vacuoles, reducing HM's translocation from roots to shoots. It enhances osmolyte production, increases antioxidant enzyme activity, and improves photosynthesis, thereby improving cellular functions. Understanding the melatonin-mediated response and signalling can sustain crop production in heavy metal-stressed soils. Melatonin is a pleiotropic signal molecule that plays a critical role in plant growth and stress tolerance, particularly against heavy metals in soil. Heavy metals (HMs) are ubiquitously found in the soil-water environment and readily taken up by plants, thereby disrupting mineral nutrient homeostasis, osmotic balance, oxidative stress, and altered primary and secondary metabolism. Plants combat HM stress through inbuilt defensive mechanisms, such as metal exclusion, restricted foliar translocation, metal sequestration and compartmentalization, chelation, and scavenging of free radicals by antioxidant enzymes. Melatonin has a protective effect against the damaging effects of HM stress in plants. It achieves this by immobilizing HM in cell walls and sequestering them in root cell vacuoles, reducing HM's translocation from roots to shoots. This mechanism improves the uptake of macronutrients and micronutrients in plants. Additionally, melatonin enhances osmolyte production, improving the plant's water relations, and increasing the activity of antioxidant enzymes to limit lipid peroxidation and reactive oxygen species (ROS) levels. Melatonin also decreases chlorophyll degradation while increasing its synthesis, and enhances RuBisCO activity for better photosynthesis. All these functions contribute to improving the cellular functions of plants exposed to HM stress. This review aims to gain better insight into the melatonin-mediated response and signalling under HM stress in plants, which may be useful in sustaining crop production in heavy metal-stressed soils.

Printing tissue-engineered scaffolds made of polycaprolactone and nano-hydroxyapatite with mechanical properties appropriate for trabecular bone substitutes.

BACKGROUND: Bone tissue engineering, based on three-dimensional (3D) printing technology, has emerged as a promising approach to treat bone defects using scaffolds. The objective of this study was to investigate the influence of porosity and internal structure on the mechanical properties of scaffolds. METHODS: We fabricated composite scaffolds (which aimed to replicate trabecular bone) from polycaprolactone (PCL) reinforced with 30% (wt.) nano-hydroxyapatite (nHAp) by extrusion printing. Scaffolds with various porosities were designed and fabricated with and without an interlayer offset, termed as staggered and lattice structure, respectively. Mechanical compressive testing was performed to determine scaffold elastic modulus and yield strength. Linear regression was used to evaluate mechanical properties as a function of scaffold porosity. RESULTS: Different relationships between mechanical properties and porosities were noted for the staggered and lattice structures. For elastic moduli, the two relationships intersected (porosity = 55%) such that the lattice structure exhibited higher moduli with porosity values greater than the intersection point; vice versa for the staggered structure. The lattice structure exhibited higher yield strength at all porosities. Mechanical testing results also indicated elastic moduli and yield strength properties comparable to trabecular bone (elastic moduli: 14-165 MPa; yield strength: 0.9-10 MPa). CONCLUSIONS: Taken together, this study demonstrates that scaffolds printed from PCL/30% (wt.) nHAp with lattice and staggered structure offer promise for treating trabecular bone defects. This study identified the effect of porosity and internal structure on scaffold mechanical properties and provided suggestions for developing scaffolds with mechanical properties for substituting trabecular bone.

Multitarget Potential of Phytochemicals from Traditional Medicinal Tree, Terminalia arjuna (Roxb. ex DC.) Wight & Arnot as Potential Medicaments for Cardiovascular Disease: An In-Silico Approach.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna, that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

Glans Anthropometry for Preputial Reconstruction in Hypospadias.

Background: Cases of hypospadias present for poor stream or cosmetic appearance. The main aim is to provide a visibly normal phallus. Preputial reconstruction is technical. A properly planned reconstruction based on anthropometry may improve the result. We are presenting our experience of reconstruction based on glans anthropometry. Aim: The aim of the study was to evaluate the importance of glans anthropometry in preputial reconstruction in cases of hypospadias. Materials and Methods: All cases of hypospadias operated between June 2014 and March 2022 were included. Glans width was measured at the base. The marking sutures for preputial reconstruction were taken at distance thrice the glans width at base. Those requiring religious circumcision along with repair, associated significant chordee, catheter came out before 2 weeks, or history of any previous penile surgery were excluded. All the cases were subjected to urethroplasty, meatoplasty, and preputioplasty. The results obtained were analyzed. Results: One hundred and forty-eight out of 159 cases formed the study group. There were 31 glanular, 42 distal penile, 58 mid-penile, and 17 proximal penile hypospadias. Mean glans width at base was 16 mm (range: 11-21 mm). Mean distance of marking suture at prepuce was 38 mm (range: 33-63 mm). Mean follow-up was 12 months (range: 1-36 months). Mean age at presentation was 23 months (range: 14-72 months). Mean operating time was 50 min (range: 45-60 min). Fistula at the base of preputioplasty was seen in four. Dehiscence of preputioplasty was seen in six. Meatal stenosis was seen in three cases. Conclusion: Preputial reconstruction improves the cosmetic appearance of the hypospadiac penis. Reconstruction based on glans anthropometry improves the result and avoids complications.

From source to sink: mechanistic insight of photoassimilates synthesis and partitioning under high temperature and elevated [CO2].

Photosynthesis is the vital metabolism of the plant affected by abiotic stress such as high temperature and elevated [CO2] levels, which ultimately affect the source-sink relationship. Triose phosphate, the primary precursor of carbohydrate (starch and sucrose) synthesis in the plant, depends on environmental cues. The synthesis of starch in the chloroplasts of leaves (during the day), the transport of photoassimilates (sucrose) from source to sink, the loading and unloading of photoassimilates, and the accumulation of starch in the sink tissue all require a highly regulated network and communication system within the plant. These processes might be affected by high-temperature stress and elevated [CO2] conditions. Generally, elevated [CO2] levels enhance plant growth, photosynthetic rate, starch synthesis, and accumulation, ultimately diluting the nutrient of sink tissues. On the contrary, high-temperature stress is detrimental to plant development affecting photosynthesis, starch synthesis, sucrose synthesis and transport, and photoassimilate accumulation in sink tissues. Moreover, these environmental conditions also negatively impact the quality attributes such as grain/tuber quality, cooking quality, nutritional status in the edible parts and organoleptic traits. In this review, we have attempted to provide an insight into the source-sink relationship and the sugar metabolites synthesized and utilized by the plant under elevated [CO2] and high-temperature stress. This review will help future researchers comprehend the source-sink process for crop growth under changing climate scenarios.

Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND).

BACKGROUND: Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency. METHODS: In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0-10.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat 100 mg oral tablets thrice a week for 24 weeks or biosimilar darbepoetin subcutaneous injection 0.75 µg/kg once in 2 weeks for 24 weeks. The primary outcome was the change from baseline in hemoglobin to evaluation period of Weeks 16-24. Key secondary outcomes included the number of patients with hemoglobin response, changes in the hepcidin levels, changes in the vascular endothelial growth factor (VEGF) levels, and changes in the lipid and lipoprotein profiles. RESULTS: Hemoglobin change from baseline to Weeks 16-24 was 1.95 g/dL in the desidustat group and 1.83 g/dL in the darbepoetin group (difference: 0.11 g/dL; 95% CI: -0.12, 0.34), which met prespecified non-inferiority margin (-0.75 g/dL). The hemoglobin responders were significantly higher (p = 0.0181) in the desidustat group (196 [77.78%]) compared to the darbepoetin group (176 [68.48%]). The difference of change in hepcidin from baseline to Week 12 and Week 24 (p = 0.0032 at Week 12, p = 0.0016 at Week 24) and the difference of change in low-density lipoprotein from baseline to Week 24 (p value = 0.0269) between the two groups was statistically significant. The difference of change from baseline in VEGF to Weeks 12 and 24 between the two groups was not statistically significant. CONCLUSION: Desidustat is non-inferior to darbepoetin in the treatment of anemia due to non-dialysis dependent CKD and it is well-tolerated.

Fused ultrasound and electromyography-driven neuromuscular model to improve plantarflexion moment prediction across walking speeds.

BACKGROUND: Improving the prediction ability of a human-machine interface (HMI) is critical to accomplish a bio-inspired or model-based control strategy for rehabilitation interventions, which are of increased interest to assist limb function post neurological injuries. A fundamental role of the HMI is to accurately predict human intent by mapping signals from a mechanical sensor or surface electromyography (sEMG) sensor. These sensors are limited to measuring the resulting limb force or movement or the neural signal evoking the force. As the intermediate mapping in the HMI also depends on muscle contractility, a motivation exists to include architectural features of the muscle as surrogates of dynamic muscle movement, thus further improving the HMI's prediction accuracy. OBJECTIVE: The purpose of this study is to investigate a non-invasive sEMG and ultrasound (US) imaging-driven Hill-type neuromuscular model (HNM) for net ankle joint plantarflexion moment prediction. We hypothesize that the fusion of signals from sEMG and US imaging results in a more accurate net plantarflexion moment prediction than sole sEMG or US imaging. METHODS: Ten young non-disabled participants walked on a treadmill at speeds of 0.50, 0.75, 1.00, 1.25, and 1.50 m/s. The proposed HNM consists of two muscle-tendon units. The muscle activation for each unit was calculated as a weighted summation of the normalized sEMG signal and normalized muscle thickness signal from US imaging. The HNM calibration was performed under both single-speed mode and inter-speed mode, and then the calibrated HNM was validated across all walking speeds. RESULTS: On average, the normalized moment prediction root mean square error was reduced by 14.58 % ([Formula: see text]) and 36.79 % ([Formula: see text]) with the proposed HNM when compared to sEMG-driven and US imaging-driven HNMs, respectively. Also, the calibrated models with data from the inter-speed mode were more robust than those from single-speed modes for the moment prediction. CONCLUSIONS: The proposed sEMG-US imaging-driven HNM can significantly improve the net plantarflexion moment prediction accuracy across multiple walking speeds. The findings imply that the proposed HNM can be potentially used in bio-inspired control strategies for rehabilitative devices due to its superior prediction.

Ultrasound Echogenicity as an Indicator of Muscle Fatigue during Functional Electrical Stimulation.

Functional electrical stimulation (FES) is a potential neurorehabilitative intervention to enable functional movements in persons with neurological conditions that cause mobility impairments. However, the quick onset of muscle fatigue during FES is a significant challenge for sustaining the desired functional movements for more extended periods. Therefore, a considerable interest still exists in the development of sensing techniques that reliably measure FES-induced muscle fatigue. This study proposes to use ultrasound (US) imaging-derived echogenicity signal as an indicator of FES-induced muscle fatigue. We hypothesized that the US-derived echogenicity signal is sensitive to FES-induced muscle fatigue under isometric and dynamic muscle contraction conditions. Eight non-disabled participants participated in the experiments, where FES electrodes were applied on their tibialis anterior (TA) muscles. During a fatigue protocol under either isometric and dynamic ankle dorsiflexion conditions, we synchronously collected the isometric dorsiflexion torque or dynamic dorsiflexion angle on the ankle joint, US echogenicity signals from TA muscle, and the applied stimulation intensity. The experimental results showed an exponential reduction in the US echogenicity relative change (ERC) as the fatigue progressed under the isometric (R2=0.891±0.081) and dynamic (R2=0.858±0.065) conditions. The experimental results also implied a strong linear relationship between US ERC and TA muscle fatigue benchmark (dorsiflexion torque or angle amplitude), with R2 values of 0.840±0.054 and 0.794±0.065 under isometric and dynamic conditions, respectively. The findings in this study indicate that the US echogenicity signal is a computationally efficient signal that strongly represents FES-induced muscle fatigue. Its potential real-time implementation to detect fatigue can facilitate an FES closed-loop controller design that considers the FES-induced muscle fatigue.

Evaluation of the Antifungal, Antioxidant, and Anti-Diabetic Potential of the Essential Oil of Curcuma longa Leaves from the North-Western Himalayas by In Vitro and In Silico Analysis.

Essential oils (EOs) have gained immense popularity due to considerable interest in the health, food, and pharmaceutical industries. The present study aimed to evaluate the antimicrobial and antioxidant activity and the anti-diabetic potential of Curcuma longa leaf (CLO) essential oil. Further, major phytocompounds of CLO were analyzed for their in-silico interactions with antifungal, antioxidant, and anti-diabetic proteins. CLO was found to have a strong antifungal activity against the tested Candida species with zone of inhibition (ZOI)-11.5 ± 0.71 mm to 13 ± 1.41 mm and minimum inhibitory concentration (MIC) was 0.63%. CLO also showed antioxidant activity, with IC50 values of 5.85 ± 1.61 µg/mL using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay and 32.92 ± 0.64 µM using ferric reducing antioxidant power (FRAP) assay. CLO also showed anti-diabetic activity with an IC50 of 43.06 ± 1.24 µg/mL as compared to metformin (half maximal inhibitory concentration, IC50-16.503 ± 0.66 µg/mL). Gas chromatography-mass spectrometry (GC-MS) analysis of CLO showed the presence of (-)-zingiberene (17.84%); 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene)-(15.31%); cyclohexene, 4-methyl-3-(1-methylethylidene) (12.47%); and (+)-4-Carene (11.89%) as major phytocompounds. Molecular docking of these compounds with antifungal proteins (cytochrome P450 14 alpha-sterol demethylase, PDB ID: 1EA1, and N-myristoyl transferase, PDB ID: 1IYL), antioxidant (human peroxiredoxin 5, PDB ID: 1HD2), and anti-diabetic proteins (human pancreatic alpha-amylase, PDB ID: 1HNY) showed strong binding of 3,7-cyclodecadien-1-one with all the selected protein targets. Furthermore, molecular dynamics (MD) simulations for a 100 ns time scale revealed that most of the key contacts of target proteins were retained throughout the simulation trajectories. Binding free energy calculations using molecular mechanics generalized born surface area (MM/GBSA), and drug-likeness and toxicity analysis also proved the potential for 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene) to replace toxic synthetic drugs and act as natural antioxidants.

An Iterative Learning Controller for a Switched Cooperative Allocation Strategy during Sit-to-Stand Tasks with a Hybrid Exoskeleton.

A hybrid exoskeleton that combines functional electrical stimulation (FES) and a powered exoskeleton is an emerging technology for assisting people with mobility disorders. The cooperative use of FES and the exoskeleton allows active muscle contractions via FES while robustifying torque generation to reduce FES-induced muscle fatigue. In this paper, a switched distribution of allocation ratios between FES and electric motors in a closed-loop adaptive control design is explored for the first time. The new controller uses an iterative learning neural network (NN)-based control law to compensate for structured and unstructured parametric uncertainties in the hybrid exoskeleton model. A discrete Lyapunov-like stability analysis that uses a common energy function proves asymptotic stability for the switched system with iterative learning update laws. Five human participants, including a person with complete spinal cord injury, performed sit-to-stand tasks with the new controller. The experimental results showed that the synthesized controller, in a few iterations, reduced the root mean square error between desired positions and actual positions of the knee and hip joints by 46.20% and 53.34%, respectively. The sit-to-stand experimental results also show that the proposed NN-based iterative learning control (NNILC) approach can recover the asymptotically trajectory tracking performance despite the switching of allocation levels between FES and electric motor. Compared to a proportional-derivative controller and traditional iterative learning control, the findings showed that the new controller can potentially simplify the clinical implementation of the hybrid exoskeleton with minimal parameters tuning.

Study of Correlation of CD4, CD8 Count with Tuberculous Pneumonia and Non Tuberculous Bacterial Pneumonia in Type 2 Diabetes Mellitu.

AIM: Type-2 DM patients are susceptible for various types of infections. Long standing Type2 DM patients have strong predilection for tuberculosis as seen in various studies. Here, we aimed to study susceptibility of tuberculosis as compared to other non tuberculous pneumonia in type-2 DM on the basis of CD markers. MATERIAL AND METHODS: A case control study on 150 subjects was conducted in S.P. Medical College and Associated Group of P.B.M. Hospitals, Bikaner. Subjects were divided into 3 groups each of 50 type-2 diabetic patients having tuberculous pneumonia, of 50 type-2 diabetic patients having non tuberculous pneumonia and 50 patients of type 2 diabetes as a control group attending Medical Outdoor and those Admitted in Hospital IPD Wards. All participants were subjected to detailed clinical examination and relevant investigations. Flow cytometry was used for CD4 and CD8 count. RESULTS: Diabetic patients with tuberculous pneumonia have significantly (p-value <0.05) elevated numbers of CD4 and CD8 cell count in comparison of both controls and nontuberculous pneumonia. Diabetic patients with non tuberculous pneumonia have significantly (p-value <0.05) lower CD4 and CD8 cell count in comparison of diabetic controls and diabetic patients with tuberculous pneumonia. CONCLUSION: DM is associated with an alteration in the immune response to tuberculosis, leading to a induction of CD4 and CD8 mediated cellular responses and likely contributing to increased immune pathology in M. tuberculosis infection. Our study also provides an impetus to perform longitudinal studies examining the role of immunological biomarkers in the development of tuberculosis in diabetic patients.

A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG).

BACKGROUND: Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. METHODS: This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. RESULTS: A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. CONCLUSIONS: This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). CLINICAL TRIALS REGISTRATION: CTRI/2017/07/009038.

A Tube-based Model Predictive Control Method to Regulate a Knee Joint with Functional Electrical Stimulation and Electric Motor Assist.

A hybrid neuroprosthesis system is a promising rehabilitation technology to restore lower-limb function in persons with paraplegia. The technology combines functional electrical stimulation (FES) and a powered lower limb exoskeleton to produce movements for walking and standing. The main control challenge in the hybrid neuroprosthesis is to achieve an optimal coordination between FES and electric motors. Model-based optimal control methods have been suggested for the control of the hybrid neuroprosthesis. However, it is often difficult to effect robust control performance with model-based optimal control methods due to modeling uncertainties. A tube-based model predictive control (MPC) method is developed to obtain robust and optimal coordination between FES and an electric motor during a knee regulation task. An external feedback control is used to limit the error between the actual position and the MPC-computed nominal position. The tube-based MPC method is proven to have recursive feasibility, compliance to input constraints, and exponentially bounded stability. The experimental results obtained from an able-bodied participant and a participant with spinal cord injury validate the controller's ability to allocate control inputs to FES and the electric motor as well as method's robustness to modeling uncertainties.

The Impact of Ureteral Access Sheath Use on the Development of Abnormal Postoperative Upper Tract Imaging after Ureteroscopy.

PURPOSE: Ureteral access sheaths are commonly used during ureteroscopy to facilitate stone removal, improve visibility and maintain low intrarenal pressures. However, the use of a ureteral access sheath can cause ureteral wall ischemia and ureteral tears, potentially increasing the risk of postoperative ureteral stricture and obstruction. We studied the impact of ureteral access sheath use on postoperative imaging studies. Secondary objectives included studying the impact of other intraoperative parameters on postoperative imaging studies. MATERIALS AND METHODS: A retrospective chart review was conducted of cases that underwent ureteroscopy for nephroureterolithiasis across 2 high volume institutions between January 2012 and September 2016. Patient demographics, cumulative stone size, operative time, use of ureteral access sheath, laser lithotripsy, basket extraction, preoperative ureteral stent and postoperative ureteral stent placement were extracted from the electronic medical record. Findings of followup renal ultrasound, kidney-ureter-bladder x-ray and/or computerized tomography at approximately 8 weeks after surgery were recorded. RESULTS: A total of 1,332 ureteroscopies were performed with 1,060 cases (79.6%) returning for routine upper tract imaging after ureteroscopy. Postoperative hydronephrosis was noted following 127 cases (12.0%). Factors predicting presence of hydronephrosis after ureteroscopy include lower body mass index (p=0.0016), greater cumulative stone size (p=0.0003), increased operative time (p <0.0001), preoperative ureteral stent (OR 1.49, p=0.0299) and postoperative ureteral stent placement (OR 6.43, p=0.0031). Postoperative hydronephrosis was not associated with use of ureteral access sheath, age, laser lithotripsy or basket extraction. CONCLUSIONS: Use of ureteral access sheath did not have a significant impact on development of postoperative hydronephrosis, suggesting ureteral access sheath is safe for use during ureteroscopy. Ureteral strictures remain rare following ureteroscopy, seen in only 1.0% of our cohort. With an observed prevalence of hydronephrosis of 12.0% on followup imaging at 8 weeks, routine upper tract imaging after ureteroscopy remains a valuable prognostic tool.

Filgrastim loading in PLGA and SLN nanoparticulate system: a bioinformatics approach.

OBJECTIVE: In this research work, we hypothesized to predict the nanoparticulate system, best suited for targeted delivery of filgrastim. Significance: Targeted delivery of filgrastim to bone marrow is required to decrease the incidence of neutropenia/febrile neutropenia. This is achieved by nanoparticulate systems, duly designed by bioinformatics approach. METHOD: The targeted delivery of filgrastim in nanoparticulate system was achieved by molecular dynamics (MD) simulation studies. Two matrices comprising PLGA and SLN (tripalmitin, core component of SLN system) were modeled separately with proposed drug filgrastim. Energy minimization of all systems was done using the steepest descent method. PLGA and tripalmitin systems were equalized at 310 °C, at 1 bar pressure with Berendsen barostat for 200 ps using a v-rescale thermostat for 100 ps. Atomistic MD simulations of four model system and mass density of interacting systems were calculated. RESULTS: The mass density maps of each nanoparticle system, that is, PLGA and tripalmitin showed an increase in density toward the end of the simulation. The contact numbers attained equilibria with the average number of approx.. 1500 contacts in case of tripalmitin-filgrastim system. While PLGA-filgrastim system shows lesser contacts as compared to tripalmitin with average contacts of approx. 1000.The binding free energy was predicted to be -1104 kJ/mol in tripalmitin-filgrastim complex and -421 kJ/mol in PLGA-filgrastim system. CONCLUSION: Findings of study revealed that both nanoparticle systems assumed to be good model for drug-carrier systems. Though SLN systems were thought to be more appropriate than PLGA, still the in vivo findings could ascertain this hypothesis in futuristic work.

Enhancement in brain uptake of vitamin D3 nanoemulsion for treatment of cerebral ischemia: formulation, gamma scintigraphy and efficacy study in transient middle cerebral artery occlusion rat models.

AIM: For the treatment of cerebral ischaemia, vitamin-D3 loaded nanoemulsions were developed. METHOD: Tween 20 and polyethylene glycol were chosen as surfactant/co-surfactant, while oleic acid as the oil phase. The formulation was characterised for various in-vitro parameters. Targeting efficiency was investigated through radiometry, gamma scintigraphy and efficacy was studied in transient middle cerebral artery occlusion (MCAo) rat model. RESULT: Vitamin D3-nanoemulsion showed a mean size range of 49.29 ± 10.28 nm with polydispersity index 0.17 ± 0.04 and zeta potential 13.77 mV. The formulation was found stable during thermodynamic stability study and permeated within 180 min through sheep nasal mucosa (permeation coefficient 7.873 ± 0.884 cm/h). Gamma scintigraphy and radiometry assay confirmed better percentage deposition (2.53 ± 0.17%) of 99mTc-vitamin D3-nanoemulsion through nasal route compared to IV administered 99mTc-vitamin D3 solution (0.79 ± 0.03%). Magnetic Resonance Imaging (MRI) of the ischaemic model confirmed better efficacy of vitamin D3-nanoemulsion. CONCLUSION: This work demonstrated better permeation, deposition, and efficacy of vitaminD3-nanoemulsion through the intranasal route.