Progress and trends in neurological disorders research based on deep learning.

In recent years, deep learning (DL) has emerged as a powerful tool in clinical imaging, offering unprecedented opportunities for the diagnosis and treatment of neurological disorders (NDs). This comprehensive review explores the multifaceted role of DL techniques in leveraging vast datasets to advance our understanding of NDs and improve clinical outcomes. Beginning with a systematic literature review, we delve into the utilization of DL, particularly focusing on multimodal neuroimaging data analysis-a domain that has witnessed rapid progress and garnered significant scientific interest. Our study categorizes and critically analyses numerous DL models, including Convolutional Neural Networks (CNNs), LSTM-CNN, GAN, and VGG, to understand their performance across different types of Neurology Diseases. Through particular analysis, we identify key benchmarks and datasets utilized in training and testing DL models, shedding light on the challenges and opportunities in clinical neuroimaging research. Moreover, we discuss the effectiveness of DL in real-world clinical scenarios, emphasizing its potential to revolutionize ND diagnosis and therapy. By synthesizing existing literature and describing future directions, this review not only provides insights into the current state of DL applications in ND analysis but also covers the way for the development of more efficient and accessible DL techniques. Finally, our findings underscore the transformative impact of DL in reshaping the landscape of clinical neuroimaging, offering hope for enhanced patient care and groundbreaking discoveries in the field of neurology. This review paper is beneficial for neuropathologists and new researchers in this field.

Weighing the Impact: The Influence of Body Mass Index on Facility Costs in Total Joint Arthroplasty.

BACKGROUND: Using time-driven activity-based costing (TDABC), a novel cost calculation method that more accurately reflects true resource utilization in healthcare, we sought to compare the total facility costs across different body mass index (BMI) groups following total joint arthroplasty (TJA). METHODS: The study consisted of 13,806 TJAs (7,340 TKAs and 6,466 THAs) performed between 2019 and 2023. The TDABC data from an analytics platform was employed to depict total facility costs, comprising personnel and supply costs. For the analysis, patients were stratified into four BMI categories: < 30, 30 to < 35, 35 to < 40, and ≥ 40. Multivariable regression was used to determine the independent effect of BMI on facility costs. RESULTS: When indexed to patients who had BMI < 30, elevated BMI categories (30 to < 35, 35 to <40, and ≥ 40) were associated with higher total personnel costs (TKA 1.03x versus 1.07x versus 1.13x, P < 0.001; THA 1.00x versus 1.08x versus 1.08x, P < 0.001), and total supply costs (TKA 1.01x versus 1.04x versus 1.04x, P < 0.001; THA 1.01x versus 1.02x versus 1.03x, P = 0.007). Total facility costs in TJAs were significantly greater in higher BMI categories (TKA 1.02x versus 1.05x versus 1.08x, P < 0.001; THA 1.01x vs. 1.05x vs. 1.05x, P < 0.001). Notably, when incorporating adjustments for demographics and comorbidities, BMI values of 35, 40, and 45 relative to BMI of 25, exhibit a significant association with a 2, 3, and 5% increase in total facility cost for TKAs and a 3, 5, and 7% increase for THAs. CONCLUSIONS: Using TDABC methodology, this study found that overall facility costs of TJAs increase with BMI. The present study provides patient-level cost insights, indicating the potential need for reassessment of physician compensation models in this population. Further studies may facilitate the development of risk-adjusted procedural codes and compensation models for public and private payors.

Intravitreal Infliximab for the Treatment of Proliferative Vitreoretinopathy (FIXER): A Randomized Controlled Phase 2 Trial.

OBJECTIVE: To study the safety and efficacy of intravitreal infliximab administered at the conclusion of pars plana vitrectomy (PPV) in the treatment of proliferative vitreoretinopathy (PVR) associated with rhegmatogenous retinal detachment (RRD). DESIGN: Randomized controlled phase 2 clinical trial. SUBJECTS: Patients with primary RRD and Grade C PVR, according to the updated Retina Society Classification. METHODS: Sixty-six Patients were randomized in a 1:1 ratio to undergo PPV and silicone oil (SO) injection with or without intravitreal injection of 1 mg/0.05 mL of infliximab in the air-filled globe before SO injection at PPV conclusion. Surgeons were masked to treatment allocation until PPV conclusion. MAIN OUTCOME MEASURES: The primary outcome measure was anatomic success (defined as complete retinal reattachment without a tamponade at 6 months post SO removal). Secondary outcome measures were final best corrected visual acuity (BCVA), single operation success rate (SOSR), rate of recurrent detachment, central macular thickness (CMT) by macular optical coherence tomography (OCT), macular function by multifocal electroretinogram and macular vascular density (VD) by OCT angiography. RESULTS: 60 eyes of 60 patients, 30 eyes in each group, completed the study. At baseline, there were no differences regarding age, gender, history of trauma, lens status, duration of RRD, BCVA, intraocular pressure (IOP), intra-ocular inflammation (IOI), detachment extent in clock hours, number/size of breaks, presence of vitreous hemorrhage, axial length, or grade/extent of PVR between both groups. For the outcome measures, 30 eyes in the infliximab group achieved anatomic success vs 29 eyes in the control group. The SOSR was higher in the infliximab group (26) vs the control (23), but this was not statistically significant (p = 0.317). Final BCVA was better in the infliximab group (mean logMAR (SD) = 0.96 (0.4), Snellen equivalent ≈ 20/180) vs the control (1.14 (0.4), Snellen equivalent ≈ 20/280) (p = 0.044). There were no differences regarding IOP, IOI, time of SO removal, macular function, CMT, or VD. CONCLUSION: PPV with SO tamponade with or without intravitreal infliximab is effective in treating PVR-associated RRD. Infliximab may be associated with modest improvement in final visual outcomes but not anatomical outcomes.

Effect of Bio-Fertilizer Application on Agronomic Traits, Yield, and Nutrient Uptake of Barley (Hordeum vulgare) in Saline Soil.

Under salinity conditions, growth and productivity of grain crops decrease, leading to inhibition and limited absorption of water and elements necessary for plant growth, osmotic imbalance, ionic stress, and oxidative stress. Microorganisms in bio-fertilizers have several mechanisms to provide benefits to crop plants and reduce the harmful effect of salinity. They can be effective in dissolving phosphate, fixing nitrogen, promoting plant growth, and can have a combination of all these qualities. During two successful agricultural seasons, two field experiments were conducted to evaluate the effect of bio-fertilizer applications, including phosphate solubilizing bacteria (PSB), nitrogen fixation bacteria and a mix of phosphate-solubilizing bacteria and nitrogen fixation bacteria with three rates, 50, 75 and 100% NPK, of the recommended dose of minimal fertilizer on agronomic traits, yield and nutrient uptake of barley (Hordeum vulgare) under saline condition in Village 13, Farafra Oasis, New Valley Governorate, Egypt. The results showed that the application of Microbein + 75% NPK recorded the highest values of plant height, spike length, number of spikes/m2, grain yield (Mg ha-1), straw yield (Mg ha-1), biological yield (Mg ha-1), protein content %, nitrogen (N), phosphorus (P), potassium (K) uptakes in grain and straw (kg ha-1), available nitrogen (mg/kg soil), available phosphorus (mg/kg soil), total microbial count of soil, antioxidant activity of soil (AOA), dehydrogenase, nitrogen fixers, and PSB counts. The application of bio-fertilizers led to an increase in plant tolerance to salt stress, plant growth, grain yield, and straw yield, in addition to the application of the bio-fertilizers, which resulted in a 25% saving in the cost of mineral fertilizers used in barley production.

Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

A study into how thickness, infrared intensity, and airflow affect drying kinetics, modeling, activation energy, and quality attributes of apple slices using infrared dryer.

Drying is a widely recognized process that reduces the need for storage and shipping weight, keeps free water out of the product, and prolongs its shelf life. An infrared dryer was designed to dry apples under different drying conditions. Apple slices of 6-, 4-, and 2-mm thicknesses were dried at intensities 0.130, 0.225, and 0.341 W/cm2 and airflow 1.0, 0.5, and 1.5 m/s. The dehydrating period was prolonged with higher airflow and shortened with higher infrared intensity (IR). The shortest dehydrating period was verified by 190 min at 0.341 W/cm2, 0.5 m/s under 2 mm thickness. Increasing the sample thickness from 2 to 4 mm and then to 6 mm resulted in an 84% and 192% increase in drying time, respectively. Dehydrated apples had water activity values ranging from 0.30 to 0.40. The shrinkage ratio increased with an increase in infrared radiation intensity. However, it decreased with an increase in air velocity, while the rehydration ratio decreased with an increase in radiation intensity and increased with an increase in air velocity. Regarding total color change, apple slice thickness was a major factor. The effective diffusivities varied between 2.6 and 9.0 𝗑10-10 m2/s under different drying conditions. The dehydrating curves of apples were best described by the model developed by Midilli et al.

AAHKS Surgical Techniques & Technologies Award: Inferior Screw Fixation Decreases Acetabular Component Failure Following Revision Total Hip Arthroplasty.

BACKGROUND: Adjunctive screw fixation has been shown to be reliable in achieving acetabular component stability in revision total hip arthroplasty (THA). The purpose of this study was to assess the effect of inferior screw placement on acetabular component failure following revision THA. We hypothesized that inferior screw fixation would decrease acetabular failure rates. METHODS: We reviewed 250 patients who had Paprosky Type II or III defects who underwent acetabular revision between 2001 and 2021 across three institutions. Demographic factors, the number of screws, location of screw placement (superior versus inferior), use of augments and/or cup-cage constructs, Paprosky classification, and presence of discontinuity were documented. Multivariate regression was performed to identify the independent effect of inferior screw fixation on the primary outcome of aseptic rerevision of the acetabular component. RESULTS: At a mean follow-up of 53.4 months (range, 12 to 261), 16 patients (6.4%) required re-revision for acetabular loosening. There were 140 patients (56.0%) who had inferior screw fixation, all of whom did not have neurovascular complications during screw placement. Patients who had inferior screws had a lower rate of acetabular rerevision than those who only had superior screw fixation (2.1 versus 11.8%, P = .0030). Multivariate regression demonstrates that inferior screw fixation decreased the likelihood of rerevision for acetabular loosening when compared to superior screw fixation alone (odds ratio: 0.1, confidence interval: 0.03 to 0.5; P = .0071). No other risk factors were identified. CONCLUSIONS: Inferior screw fixation is a safe and reliable technique to reduce acetabular component failure following revision THA in cases of severe acetabular bone loss.

Time to Achieve the Minimal Clinically Important Difference in Primary Total Hip Arthroplasty: Comparison of Anterior and Posterior Surgical Approaches.

BACKGROUND: Controversy remains over outcomes between total hip arthroplasty approaches. This study aimed to compare the time to achieve the minimal clinically important difference (MCID) for the Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form (HOOS-PS) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Global-Physical for patients who underwent anterior and posterior surgical approaches in primary total hip arthroplasty. METHODS: Patients from 2018 to 2021 with preoperative and postoperative HOOS-PS or PROMIS Global-Physical questionnaires were grouped by approach. Demographic and MCID achievement rates were compared, and survival curves with and without interval-censoring were used to assess the time to achieve the MCID by approach. Log-rank and weighted log-rank tests were used to compare groups, and Weibull regression analyses were performed to assess potential covariates. RESULTS: A total of 2,725 patients (1,054 anterior and 1,671 posterior) were analyzed. There were no significant differences in median MCID achievement times for either the HOOS-PS (anterior: 5.9 months, 95% confidence interval [CI]: 4.6 to 6.4; posterior: 4.4 months, 95% CI: 4.1 to 5.1, P = .65) or the PROMIS Global-Physical (anterior: 4.2 months, 95% CI: 3.5 to 5.3; posterior: 3.5 months, 95% CI: 3.4 to 3.8, P = .08) between approaches. Interval-censoring revealed earlier times of achieving the MCID for both the HOOS-PS (anterior: 1.509 to 1.511 months; posterior: 1.7 to 2.3 months, P = .87) and the PROMIS Global-Physical (anterior: 3.0 to 3.1 weeks; posterior: 2.7 to 3.3 weeks, P = .18) for both surgical approaches. CONCLUSIONS: The time to achieve the MCID did not differ by surgical approach. Most patients will achieve clinically meaningful improvements in physical function much earlier than previously believed. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

Applications of humic and fulvic acid under saline soil conditions to improve growth and yield in barley.

BACKGROUND: Enriching the soil with organic matter such as humic and fulvic acid to increase its content available nutrients, improves the chemical properties of the soil and increases plant growth as well as grain yield. In this study, we conducted a field experiment using humic acid (HA), fulvic acid (FA) and recommended dose (RDP) of phosphorus fertilizer to treat Hordeum vulgare seedling, in which four concentrations from HA, FA and RDP (0.0 %, 50 %, 75 % and 100%) under saline soil conditions . Moreover, some agronomic traits (e.g. grain yield, straw yield, spikes weight, plant height, spike length and spike weight) in barley seedling after treated with different concentrations from HA, FA and RDP were determined. As such the beneficial effects of these combinations to improve plant growth, N, P, and K uptake, grain yield, and its components under salinity stress were assessed. RESULTS: The findings showed that the treatments HA + 100% RDP (T1), HA + 75% RDP (T2), FA + 100% RDP (T5), HA + 50% RDP (T3), and FA + 75% RDP (T6), improved number of spikes/plant, 1000-grain weight, grain yield/ha, harvest index, the amount of uptake of nitrogen (N), phosphorous (P) and potassium (K) in straw and grain. The increase for grain yield over the control was 64.69, 56.77, 49.83, 49.17, and 44.22% in the first season, and 64.08, 56.63, 49.19, 48.87, and 43.69% in the second season,. Meanwhile, the increase for grain yield when compared to the recommended dose was 22.30, 16.42, 11.27, 10.78, and 7.11% in the first season, and 22.17, 16.63, 11.08, 10.84, and 6.99% in the second season. Therefore, under salinity conditions the best results were obtained when, in addition to phosphate fertilizer, the soil was treated with humic acid or foliar application the plants with fulvic acid under one of the following treatments: HA + 100% RDP (T1), HA + 75% RDP (T2), FA + 100% RDP (T5), HA + 50% RDP (T3), and FA + 75% RDP (T6). CONCLUSIONS: The result of the use of organic amendments was an increase in the tolerance of barley plant to salinity stress, which was evident from the improvement in the different traits that occurred after the treatment using treatments that included organic amendments (humic acid or fulvic acid).

Nanoparticles of Thiolated Xanthan Gum for the Oral Delivery of Miconazole Nitrate: In Vitro and In Vivo Evaluation.

The objective of this research was to develop a mucoadhesive delivery system that improves permeation for the administration of poorly absorbed oral medications. Thiolation of xanthan gum (XGM) was carried out by esterification with mercaptobutyric acid. Fourier-transformed infrared spectroscopy was used to confirm thiol-derivatization. Using Ellman's technique, it was revealed that the xanthan-mercaptobutyric acid conjugate had 4.7 mM of thiol groups in 2 mg/mL of polymeric solution. Using mucosa of sheep intestine, the mucoadhesive properties of XGM and thiolated xanthan gum (TXGM) nanoparticles were investigated and we found that TXGM had a longer bioadhesion time than XGM. The disulfide link that forms between mucus and thiolated XGM explains why it has better mucoadhesive properties than XGM. A study on in vitro miconazole (MCZ) release using phosphate buffer (pH 6.8) found that TXGM nanoparticles released MCZ more steadily than MCZ dispersion did. A 1-fold increase in the permeation of MCZ was observed from nanoparticles using albino rat intestine compared to MCZ. Albino rats were used to test the pharmacokinetics of MCZ, and the results showed a 4.5-fold increase in bioavailability. In conclusion, the thiolation of XGM enhances its bioavailability, controlled release of MCZ for a long period of time, and mucoadhesive activity.

Mathematical modeling of thin-layer drying kinetics and moisture diffusivity study of apple slices using infrared conveyor-belt dryer.

The drying features of apples at different infrared drying settings were investigated. The drying time, moisture-effective diffusion, and activation energy of infrared dried apples were measured experimentally and statistically as a function of slice thicknesses, radiation intensity, and air velocity. The infrared intensity of 0.225, 0.130, and 0.341 W/cm2 , slice thicknesses of 6, 4, and 2 mm, and airflow of 0.5, 1.0, and 1.5 m/s were used to dry apple slices. The data shows that the drying time reduced as IR increased, but airflow and slice thickness increased. Eight statistical factors were used to compare 11 alternative mathematical drying models. The experimentally acquired drying curves were matched to the thin-layer drying equations. According to the calculations, the Midilli et al. equation had the greatest (efficiency and R2 ) and lowest (χ2 , sum of squared errors, standard error of estimate, standard error, standard deviation of difference) values. As a result, this equation is the best for modeling the drying curves of apple slices across all drying circumstances. The optimum moisture diffusivity value varied from 2.59 to 9.07 × 10-10  m2 /s. The mean activation energy was determined to be 19.02-29.83 kJ/mol under various experimental conditions.

Mental Health Effects on the Minimal Clinically Important Difference in Total Joint Arthroplasty.

INTRODUCTION: The effect of mental health on patient-reported outcome measures is not fully understood in total joint arthroplasty (TJA). Thus, we investigated the relationship between mental health diagnoses (MHDs) and the Minimal Clinically Important Difference for Improvement (MCID-I) and Worsening (MCID-W) in primary TJA and revision TJA (rTJA). METHODS: Retrospective data were collected using relevant Current Procedural Terminology and MHDs International Classification of Diseases, 10th Revision, codes with completed Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form, Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form, Patient-reported Outcomes Measurement Information System (PROMIS)-Physical Function Short Form 10a, PROMIS Global-Mental, or PROMIS Global-Physical questionnaires. Logistic regressions and statistical analyses were used to determine the effect of a MHD on MCID-I/MCID-W rates. RESULTS: Data included 4,562 patients (4,190 primary TJAs/372 rTJAs). In primary total hip arthroplasty (pTHA), MHD-affected outcomes for Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form (MCID-I: 81% versus 86%, P = 0.007; MCID-W: 6.0% versus 3.2%, P = 0.008), Physical Function Short Form 10a (MCID-I: 68% versus 77%, P < 0.001), PROMIS Global-Mental (MCID-I: 38% versus 44%, P = 0.009), and PROMIS Global-Physical (MCID-I: 61% versus 73%, P < 0.001; MCID-W: 14% versus 7.9%, P < 0.001) versus pTHA patients without MHD. A MHD led to lower rates of MCID-I for PROMIS Global-Physical (MCID-I: 56% versus 63%, P = 0.003) in primary total knee arthroplasty patients. No effects from a MHD were observed in rTJA patients. DISCUSSION: The presence of a MHD had a prominent negative influence on pTHA patients. Patients who underwent rTJA had lower MCID-I rates, higher MCID-W rates, and lower patient-reported outcome measure scores despite less influence from a MHD. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Diagnostic Test Performances for Identifying Periprosthetic Joint Infection in Hip Hemiarthroplasty.

INTRODUCTION: Periprosthetic joint infection (PJI) is a devastating complication of hip hemiarthroplasty (HHA) that is not well-represented in the literature. Therefore, this study aimed to evaluate diagnostic markers for identifying PJI in patients after HHA and compare them with the most recent 2018 International Consensus Meeting on Musculoskeletal Infection criteria. METHODS: A total of 98 patients (64 PJIs, 65.3%) were analyzed. Patients were identified by relevant Current Procedural Terminology and International Classification of Diseases-9/10 codes from 2000 to 2021 across a single healthcare system. Preoperative or intraoperative synovial fluid nucleated cell (NC) count, synovial polymorphonuclear (PMN) percentage, serum erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), and serum white blood cell count were compared with Student t -test between aseptic and septic cohorts. Diagnostic utility and laboratory cutoff values were determined using receiver-operating characteristic curves and Youden index, respectively. RESULTS: Mean values were significantly higher in the septic cohort for synovial NC count (120,992.2 versus 1,498.0 cells/µL, P < 0.001), synovial PMN percentage (91.3% versus 56.2%, P < 0.001), serum ESR (75.6 versus 36.3 mm/hr, P < 0.001), serum CRP (20.2 versus 125.8 mg/L, P < 0.001), and serum white blood cell count (8.5 versus 11.5 cells/µL, P < 0.001). Synovial NC count, synovial PMN percentage, and serum CRP had excellent PJI discriminatory ability with an area under the curve of 0.99, 0.90, and 0.93, respectively. Optimal cutoffs were 2,700 cells/µL for synovial NC count (100% sensitivity and 94% specificity), 81.0% for synovial PMN percentage (96% sensitivity and 89% specificity), 52.0 mm/hr for serum ESR (75% sensitivity and 80% specificity), and 40.0 mg/L for serum CRP (85% sensitivity and 92% specificity). CONCLUSION: Our findings support the continued use of routine serum and synovial fluid tests for diagnosing PJI in HHA patients. Optimal cutoff values for both synovial fluid biomarkers were very close in alignment with the 2018 International Consensus Meeting criteria. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Optimal controller design for reactor core power stabilization in a pressurized water reactor: Applications of gold rush algorithm.

Nuclear energy (NE) is seen as a reliable choice for ensuring the security of the world's energy supply, and it has only lately begun to be advocated as a strategy for reducing climate change in order to meet low-carbon energy transition goals. To achieve flexible operation across a wide operating range when it participates in peak regulation in the power systems, the pressurised water reactor (PWR) NE systems must overcome the nonlinearity problem induced by the substantial variation. In light of this viewpoint, the objective of this work is to evaluate the reactor core (main component) of the NE system via different recent optimization techniques. The PWR, which is the most common form, is the reactor under investigation. For controlling the movement of control rods that correspond with reactivity for power regulation the PWR, PID controller is employed. This study presents a dynamic model of the PWR, which includes the reactor core, the upper and lower plenums, and the piping that connects the reactor core to the steam alternator is analyzed and investigated. The PWR dynamic model is controlled by a PID controller optimized by the gold rush optimizer (GRO) built on the integration of the time-weighted square error performance indicator. Additionally, to exhibit the efficacy of the presented GRO, the dragonfly approach, Arithmetic algorithm, and planet optimization algorithm are used to adjust the PID controller parameters. Furthermore, a comparison among the optimized PID gains with the applied algorithms shows great accuracy, efficacy, and effectiveness of the proposed GRO. MATLAB\ Simulink program is used to model and simulate the system components and the applied algorithms. The simulation findings demonstrate that the suggested optimized PID control strategy has superior efficiency and resilience in terms of less overshoot and settling time.

Repaglinide-Solid Lipid Nanoparticles in Chitosan Patches for Transdermal Application: Box-Behnken Design, Characterization, and In Vivo Evaluation.

Background: Repaglinide (REP) is an antidiabetic drug with limited oral bioavailability attributable to its low solubility and considerable first-pass hepatic breakdown. This study aimed to develop a biodegradable chitosan-based system loaded with REP-solid lipid nanoparticles (REP-SLNs) for controlled release and bioavailability enhancement via transdermal delivery. Methods: REP-SLNs were fabricated by ultrasonic hot-melt emulsification. A Box-Behnken design (BBD) was employed to explore and optimize the impacts of processing variables (lipid content, surfactant concentration, and sonication amplitude) on particle size (PS), and entrapment efficiency (EE). The optimized REP-SLN formulation was then incorporated within a chitosan solution to develop a transdermal delivery system (REP-SLN-TDDS) and evaluated for physicochemical properties, drug release, and ex vivo permeation profiles. Pharmacokinetic and pharmacodynamic characteristics were assessed using experimental rats. Results: The optimized REP-SLNs had a PS of 249±9.8 nm and EE of 78%±2.3%. The developed REP-SLN-TDDS demonstrated acceptable characteristics without significant aggregation of REP-SLNs throughout the casting and drying processes. The REP-SLN-TDDS exhibited a biphasic release pattern, where around 36% of the drug load was released during the first 2 h, then the drug release was sustained at around 80% at 24 h. The computed flux across rat skin for the REP-SLN-TDDS was 2.481±0.22 µg/cm2/h in comparison to 0.696±0.07 µg/cm2/h for the unprocessed REP, with an enhancement ratio of 3.56. The REP-SLN-TDDS was capable of sustaining greater REP plasma levels over a 24 h period (p<0.05). The REP-SLN-TDDS also reduced blood glucose levels compared to unprocessed REP and commercial tablets (p<0.05) in experimental rats. Conclusion: Our REP-SLN-TDDS can be considered an efficient therapeutic option for REP administration.

One-Year Postoperative Patient-Reported Outcome Measures Are Associated With Three-Year to Five-Year Postoperative Satisfaction in Total Knee Arthroplasty.

BACKGROUND: Over the past couple of decades, the definition of success after total knee arthroplasty (TKA) has shifted away from clinician-rated metrics and toward the patient's subjective experience. Therefore, understanding the aspects of patient recovery that drive 3-year to 5-year satisfaction after TKA is crucial. The aims of this study were to (1) determine the 1-year postoperative factors, specifically patient-reported outcome measures (PROMs) that were associated with 3-year and 5-year postoperative satisfaction and (2) understand the factors that drive those who are not satisfied at 1 year postoperatively to become satisfied later in the postoperative course. METHODS: This was a retrospective study of 402 TKA patients who were gathered prospectively and presented for their 1-year follow-up. Demographics were collected preoperatively and patient-reported outcomes were collected at 1, 3, and 5 years postoperatively. Logistic regressions were used to identify the factors at 1 year that were associated with 3-year and 5-year satisfaction. RESULTS: Associations between 1-year PROMs with 3-year satisfaction were observed. Longer term satisfaction at 5 years was more closely associated with EuroQol 5 Dimension Mobility, Activity Score, and Numerical Rating Scale Satisfaction. Of those who were not satisfied at 1 year, EuroQol 5 Dimension Mobility, Knee Disability Osteoarthritis Outcome Score Function in Sport and Recreation, and Satisfaction were associated with becoming satisfied at 3 years. CONCLUSION: The 1-year PROMs were found to be associated with satisfaction at 3 to 5 years after TKA. Importantly, many of the PROMs that were associated with 3-year to 5-year satisfaction, especially in those who were not originally satisfied at 1 year, were focused on mobility and activity level.

Patients Consistently Report Worse Outcomes Following Revision Total Knee Arthroplasty Compared to Primary Total Knee Arthroplasty.

BACKGROUND: Differences in patient-reported outcome measures (PROMs) between primary TKA (pTKA) and revision TKA (rTKA) have not been well-studied. Therefore, we compared pTKA and rTKA patients by the rates of achieving the Minimal Clinically Important Difference for Improvement (MCID-I) and Worsening (MCID-W). METHODS: A total of 2,448 patients (2,239 pTKAs/209 rTKAs) were retrospectively studied. Patients who completed the Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10a (PF10a), PROMIS Global-Mental, or PROMIS Global-Physical questionnaires were identified by Current Procedural Terminology (CPT) codes. Patient-reported outcome measures and MCID-I/MCID-W rates were compared. Multivariate logistic regression models measured relationships between surgery type and postoperative outcomes. RESULTS: Patients who underwent rTKA (all causes) had lower rates of improvement and higher rates of worsening compared to pTKA patients for KOOS-PS (MCID-I: 54 versus 68%, P < .001; MCID-W: 18 versus 8.6%, P < .001), PF10a (MCID-I: 44 versus 65%, P < .001; MCID-W: 22 versus 11%, P < .001), PROMIS Global-Mental (MCID-I: 34 versus 45%, P = .005), and PROMIS Global-Physical (MCID-I: 51 versus 60%, P = .014; MCID-W: 29 versus 14%, P < .001). Undergoing revision was predictive of worsening postoperatively for KOOS-PS, PF10a, and PROMIS Global-Physical compared to pTKA. Postoperative scores were significantly higher for all 4 PROMs following pTKA. CONCLUSION: Patients reported significantly less improvement and higher rates of worsening following rTKA, particularly for PROMs that assessed physical function. Although pTKA patients did better overall, the improvement rates may be considered relatively low and should prompt discussions on improving outcomes following pTKA and rTKA. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells.

Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and exhibited moderate selectivity. Moreover, activation of prodrug 6 by NTR was confirmed by liquid chromatography-mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with Escherichia coli NTR. Thus, compound 6 can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.

Dual Surgical Setup Associated with Reduced Infection Recurrence for Hip and Knee Arthroplasty After Two-Stage Exchange.

INTRODUCTION: Two-stage exchange (TSE) is the gold standard for the treatment of chronic periprosthetic joint infection (PJI) after total joint arthroplasty of the hip and knee in the United States. Failure of treatment can have devastating consequences for the patient, including poor functional outcomes, multiple further surgeries, and increased mortality. Several factors associated with infection recurrence have previously been identified in the literature. The purpose of this study was to evaluate whether the use of a dual surgical setup was associated with reduced risk of recurrence after TSE for PJI. METHODS: A retrospective study was conducted between January 2000 and December 2021 to isolate patients who underwent TSE after total joint arthroplasty of the hip and knee. Failure was defined as infection recurrence requiring surgical intervention. Demographic factors (age, sex, body mass index, smoking status, American Society of Anesthesiologists status), preoperative comorbidities (hypertension, cardiac disease, diabetes status, depression diagnosis, pulmonary disease), operating surgeon, single versus dual setup, hospital setting, use of long-term antibiotics postoperatively after TSE, aspiration data, and infecting organism were compared between cohorts using multivariate regression analysis. RESULTS: A total of 134 patients were identified who underwent TSE after diagnosis of PJI. The mean follow-up was 67.84 (range, 13 to 236) months. Dual setup (odds ratio, 0.13; confidence interval, 0.02 to 0.52; P = 0.0122) was found to be an independent predictive variable associated with a lower risk of infection recurrence. CONCLUSION: Utilization of a dual surgical setup is a low-cost modifiable risk factor associated with a lower risk of recurrence of after TSE of the hip and knee for PJI.