Unlocking the Therapeutic Potential: Sitagliptin's Multifaceted Approach in Drug-Resistant Epilepsy through a Novel Mechanism Inhibiting Protein Kinase C-γ and a Long-Term Potentiation Pathway.

Drug-resistant epilepsy is a prominent challenge in chronic neurological disorders. Valproate, commonly used to treat epilepsy, can fail due to various side effects and interactions, necessitating the exploration of alternative treatments. Our study primarily investigated sitagliptin's potential as a therapeutic agent for drug-resistant epilepsy. Employing computational modeling and enzyme assay testing, three lead compounds, emixustat, sitagliptin, and distigmine bromide, were evaluated against the target enzyme protein kinase C-γ. In vivo, experiments on a pentylenetetrazolium-induced lamotrigine-resistant epilepsy model were conducted to test sitagliptin's antiseizure effects, compared with the standard phenobarbital treatment. Emixustat and sitagliptin showcased strong inhibitory properties, while distigmine bromide was less effective in the enzyme assay. Mechanistic insights revealed sitagliptin's ability to modulate the seizure grade and first myoclonic jerk latency via oxidative stress markers, like reduced glutathione and glutathione peroxidase emphasizing its antioxidative role in epilepsy. Additionally, it demonstrated anti-inflammatory effects by significantly reducing proinflammatory markers interleukin-1ß and interleukin-6. The modulation of key genes of the long-term potentiation pathway, particularly protein kinase C-γ and metabotropic glutamate receptor 5, was evident through mRNA expression levels. Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-γ.

Comparison of Interventions for Lateral Elbow Tendinopathy: A Systematic Review and Network Meta-Analysis for Patient-Rated Tennis Elbow Evaluation Pain Outcome.

PURPOSE: There is controversy regarding the optimal treatment for lateral elbow tendinopathy (LET), and not all available treatment options have been compared directly with placebo/control. A network meta-analysis was conducted to compare the effectiveness of different LET treatments directly and indirectly against control/placebo based on a validated outcome, the Patient-Rated Tennis Elbow Evaluation (PRTEE) pain score. METHODS: Randomized, controlled trials comparing different treatment methods for LET were included, provided they reported outcome data using the PRTEE pain score. A network meta-analysis with random effect was used to combine direct and indirect evidence between treatments compared with placebo in the short term (up to six weeks) and midterm (more than six weeks and up to six months) after intervention. RESULTS: Thirteen studies with 12 comparators including control/placebo were eligible. The results indicated no significant improvement in PRTEE pain score in the short term across all treatments compared with control/placebo. In the midterm, physiotherapy/exercise showed benefit against placebo (mean difference: -4.32, 95% confidence interval: -7.58 and -1.07). Although steroid injections, dry needling, and autologous blood also exhibited potential treatment effects, it is crucial for the clinician to consider certain pitfalls when considering these treatments. The limited number of small studies and paucity of data call for caution in interpreting the results and need for further evidence. CONCLUSIONS: Patients should be informed that there is currently no strong evidence that any treatment produces more rapid improvement in pain symptoms when compared with control/placebo in the short and medium terms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

A protocol for the conduct of a multicentre, prospective, randomized superiority trial of surgical versus non-surgical interventions for humeral shaft fractures.

Aims: Fractures of the humeral shaft represent 3% to 5% of all fractures. The most common treatment for isolated humeral diaphysis fractures in the UK is non-operative using functional bracing, which carries a low risk of complications, but is associated with a longer healing time and a greater risk of nonunion than surgery. There is an increasing trend to surgical treatment, which may lead to quicker functional recovery and lower rates of fracture nonunion than functional bracing. However, surgery carries inherent risk, including infection, bleeding, and nerve damage. The aim of this trial is to evaluate the clinical and cost-effectiveness of functional bracing compared to surgical fixation for the treatment of humeral shaft fractures. Methods: The HUmeral SHaft (HUSH) fracture study is a multicentre, prospective randomized superiority trial of surgical versus non-surgical interventions for humeral shaft fractures in adult patients. Participants will be randomized to receive either functional bracing or surgery. With 334 participants, the trial will have 90% power to detect a clinically important difference for the Disabilities of the Arm, Shoulder and Hand questionnaire score, assuming 20% loss to follow-up. Secondary outcomes will include function, pain, quality of life, complications, cost-effectiveness, time off work, and ability to drive. Discussion: The results of this trial will provide evidence regarding clinical and cost-effectiveness between surgical and non-surgical treatment of humeral shaft fractures. Ethical approval has been obtained from East of England - Cambridge Central Research Ethics Committee. Publication is anticipated to occur in 2024.

Surgical management of cubital tunnel syndrome: A systematic review and meta-analysis of randomised trials.

Background: Cubital tunnel syndrome (CUTS) is a common upper limb compression neuropathy with significant consequences when left untreated. Surgical decompression remains gold-standard treatment for moderate to severe disease, however the optimal operative technique remains unclear. This network meta-analysis (NMA) of Level I and II randomised prospective studies aims to discern superiority between open in-situ, endoscopic and anterior transposition (subcutaneous or submuscular techniques) with respect to the primary outcome of response-to-treatment and secondary outcomes which include complications, post-operative chronic pain VAS scale, return to work and re-operation. Methods: This NMA adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed, Web of Science, Cochrane Central, Science direct and Embase were searched. The MESH database was further searched with the terms 'cubital tunnel' to improve sensitivity of the search. Data pertaining to the primary and secondary outcomes were pooled for NMA. Results: Following abstract and full-text screening, 10 randomised prospective trials were included. There was no statistical difference in the response-to-treatment between the four studied techniques. Endoscopic decompression conferred a significantly higher complication rate compared to open decompression (Odds Ratio [OR], 4.21; 95% CI, 1.22-14.59). Endoscopic decompression had a statistically significant lower risk of post-operative chronic pain compared to open in-situ decompression (OR, 0.03, 95% CI, 0.00-0.32). There were no differences between techniques with respect to return to work or re-operation rates. Conclusion: Response-to-treatment was similar between the four operative techniques for CUTS. Endoscopic decompression was found to be more hazardous when compared to open-in situ decompression but conferred significantly less post-operative chronic pain. There was significant heterogeneity in reported outcomes between the included articles. The authors suggest conducting more high-quality research with standardised outcome reporting to facilitate comparison. Level of evidence ii: Systematic Review and Meta-analysis of Randomised Prospective Trials- Therapeutic study.

Understanding the Food Environment and Its Impact on Diet and Health in Asia: A Scoping Review.

Food environment (FE), an interface where people interact with a broader food system, is critical to health. Understanding the Asian FE may help to tackle the "triple burden of malnutrition" through informed research and policy. This review identifies FE domains assessed in the Asian context and collates the tools/measures used in these evaluations. We further synthesized the reported associations of FE with diet and health outcomes and identified knowledge gaps. Forty-two articles were reviewed (East Asia, n = 25, 60%; South Asia, n = 8, 19%; and Southeast Asia, n = 9, 21%). The results showed that FE was frequently examined in children, adolescents, or adults, but data were scarce in older adults. Food availability (n = 30) and accessibility (n = 19) were popularly studied domains. Furthermore, FE was measured using geographic information systems (n = 18), market (n = 7), or stakeholder (n = 21) surveys. Twenty-eight (67%) articles assessed associations of FE exposures with diet (n = 12) and health (n = 21). Increased food availability and accessibility were associated with poorer dietary and health outcomes despite nonexisting validity and reliability reporting in 62% of articles. Limited high-quality studies emphasize the need for harmonized definitions, better study designs, and validated FE measures/tools in Asia. Improving the quality of FE research is critical to designing effective interventions to improve public health nutrition in Asia.

Feasibility of Using a GENEActiv Accelerometer with Triaxial Acceleration and Temperature Sensors to Monitor Adherence to Shoulder Sling Wear Following Surgery.

BACKGROUND: Self-reported adherence to sling wear is unreliable due to recall bias. We aim to assess the feasibility and accuracy of quantifying sling wear and non-wear utilising slings pre-fitted with a GENEActiv accelerometer that houses triaxial acceleration and temperature sensors. METHODS: Ten participants were asked to wear slings for 480 min (8 h) incorporating 180 min of non-wear time in durations varying from 5-120 min. GENEActiv devices were fitted in sutured inner sling pockets and participants logged sling donning and doffing times. An algorithm based on variability in acceleration in three axes and temperature change was developed to identify sling wear and non-wear and compared to participants' logs. RESULTS: There was no significant difference between algorithm detected non-wear duration (mean ± standard deviation = 172.0 ± 6.8 min/participant) and actual non-wear (179.7 ± 1.0 min/participant). Minute-by-minute agreement of sensor-detected wear and non-wear with participant reported wear was 97.3 ± 1.5% (range = 93.9-99.0), with mean sensitivity 94.3 ± 3.5% (range = 86.1-98.3) and specificity 99.1 ± 0.8% (range = 93.7-100). CONCLUSION: An algorithm based on accelerometer-assessed acceleration and temperature can accurately identify shoulder sling wear/non-wear times. This method may have potential for assessing whether sling wear adherence after shoulder surgeries have any bearing on patient functional outcomes.

Surgical management of SLAP lesions: Which technique has better surgical outcomes?

Background: The gold-standard surgical management for superior labral anterior to posterior (SLAP) lesions is unclear. This meta-analysis compares the outcomes of different surgical SLAP lesion management techniques including labral repair, long head of biceps (LHB) tenodesis and LHB tenotomy with consideration to clinical scores, return to sports, re-operation, range-of-motion and patient satisfaction. Methods: PRISMA guidelines were adhered. Web of Science, PubMed, Cochrane Central, Science direct and EMBASE were searched using relevant keywords. Eligible studies were screened, data extracted and synthesised using Review Manager (Version 5.4.1). Bayesian network meta-analysis (NMA) was conducted. Randomised control and clinical trials regarding SLAP lesion management in patients over 18 years old were included. Studies were excluded if patients had concomitant massive tears of the rotator cuff, Bankart lesions or instability of the shoulder. Results: Patient satisfaction with LHB tenodesis was superior to superior labral repair. No difference was demonstrated with respect to ASES score, pain VAS score, return to sports and pre-injury activities, reoperation rate or range-of-motion. LHB tenodesis and LHB tenotomy show no difference in ASES score or post operative deformity in management of SLAP lesions. Discussion: High-quality, standardised randomised control studies between the different surgical techniques is warranted.

Postoperative mobilization after terrible triad injury: systematic review and single-arm meta-analysis.

BACKGROUND: Terrible triad injury is a complex injury of the elbow, involving elbow dislocation with associated fracture of the radial head, avulsion or tear of the lateral ulnar collateral ligament, and fracture of the coronoid. These injuries are commonly managed surgically with fixation or replacement of the radial head and repair of the collateral ligaments with or without fixation of the coronoid. Postoperative mobilization is a significant factor that may affect patient outcomes; however, the optimal postoperative mobilization protocol is unclear. This study aimed to systematically review the available literature regarding postoperative rehabilitation of terrible triad injuries to aid clinical decision making. METHODS: We systematically reviewed the PubMed, Embase, Cochrane, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The inclusion criteria were studies with populations aged ≥16 years with terrible triad injury in which operative treatment was performed, a clear postoperative mobilization protocol was defined, and the Mayo Elbow Performance Score (MEPS) was reported. Secondary outcomes were pain, instability, and range of motion (ROM). Postoperative mobilization was classified as either "early," defined as active ROM commencement before or up to 14 days, or "late," defined as active ROM commencement after 14 days. RESULTS: A total of 119 articles were identified from the initial search, of which 11 (301 patients) were included in the final review. The most common protocols (6 studies) favored early mobilization, whereas 5 studies undertook late mobilization. Meta-regression analysis including mobilization as a covariate showed an estimated mean difference in the pooled mean MEPS between early and late mobilization of 6.1 (95% confidence interval, 0.2-12) with a higher pooled mean MEPS for early mobilization (MEPS, 91.2) than for late mobilization (MEPS, 85; P = .041). Rates of instability reported ranged from 4.5% to 19% (8%-11.5% for early mobilization and 4.5%-19% for late mobilization). CONCLUSION: Our findings suggest that early postoperative mobilization may confer a benefit in terms of functional outcomes following surgical management of terrible triad injuries without appearing to confer an increased instability risk. Further research in the form of randomized controlled trials between early and late mobilization is advised to provide a higher level of evidence.

Integrated in-silico and in-vitro assessments of HDAC6 inhibitor efficacy in mitigating amyloid beta pathology in Alzheimer's disease.

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aß) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aß degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aß build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aß load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aß accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.

Effect of blended self-directed learning on nursing students: Quasi-experimental approach.

BACKGROUND: Higher education institutions are adapting and innovating like never before to provide highly individualized learning environments for both traditional and non-traditional students. This seismic upheaval in the higher education landscape is being observed across the world. The present study aimed to evaluate the effectiveness of a blended learning approach on nursing students' self-directed learning readiness. MATERIALS AND METHODS: This study is a quasi-experimental approach in which a non-equivalent control group was used in a post-test design. A comparison was carried out with two separate semester cohort students representing the control and intervention groups which had 24 and 30 students, respectively. This study included first-year nursing students that enrolled in a course called "Anatomy and Physiology" course of nursing education at a private university. The control group received all their teaching face-to-face, and the intervention group used information technology and prescribed activities in their online e-book. The self-directed learning readiness (SDLR) tool measures the learners' readiness in self-directed learning in both groups. This scale comprises three subscales which are "self-management," "desire for learning," and "self-control." An independent-samples t-test was conducted to compare self-directed learning readiness in the control and intervention groups. Data were analyzed using IBM SPSS Statistics 25 software to measure the independent t-test. RESULTS: The self-directed readiness scores were significantly higher in the intervention group with P = 0.019. The intervention group showed a higher mean value on the subscales of self-management and self-control, which demonstrated a significant difference with P values of 0.018 and 0.028, respectively. The subscale desire for learning was insignificant with a P value of 0.166. CONCLUSION: This study concluded that the overall results demonstrate that incorporating blended learning using e-books for anatomy and physiology courses in nursing education can contribute to students' readiness for self-directed learning. Specifically, the blended learning teaching and learning strategy had a positive impact on nursing students' capacity for self-management and self-control.

Proximal humerus fractures: A review of current practice.

The management of proximal humeral fractures (PHF) remains controversial. Its incidence is increasing. Patients should be meticulously assessed clinically for co-morbidities and neuro-vascular injuries. Radiological investigation helps provide information on the fracture configuration and dislocations. Enhanced by 3-dimensional CT scanning, these further help in decision making and operative planning. PHF classifications have been demonstrated to have poor intra-observer and inter-observer reliability. Research has identified some radiographic predictive factors for humeral head ischaemia and likely failure of surgical fixation. The range of management options include non-operative treatment, operative fixation, intramedullary nailing and arthroplasty (hemiarthroplasty, reverse shoulder replacement). The majority of PHFs are stable injuries and non-operative management is usually successful. Some degree of malunion is readily tolerated especially by elderly patients. Surgical management of significantly displaced, unstable proximal humerus fractures should aim to stabilise the fracture adequately and provide satisfactory function for the long term. Management of the greater tuberosity is pivotal for the eventual outcome. When fixation may appear to be compromised by poor bone quality, likely poor function, age related rotator cuff degeneration or likely humeral head ischaemia clinicians may opt for arthroplasty. Successful hemiarthroplasty outcomes are dependent on sufficient healing of the tuberosity and recovery of the rotator cuff integrity. Reverse shoulder replacement can predictably deliver good functional outcomes for the shoulder in elderly patients, where rotator cuff dysfunction is suspected or as a revision procedure following failure of other surgical interventions. As opposed to hemiarthroplasty, which has shown a downward trend, there has been an increasing trend towards the use of reverse shoulder replacement in proximal humeral fractures. The management of PHFs should be patient specific, fracture specific and meet the functional demands and needs of the individual patient. The surgeon's skill set and clinical experience also plays an important role in the options of management available.

BESS patient care pathway: Tennis elbow.

This article provides a guidance summary for the management of lateral elbow tendinopathy (LET) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of the rating quality of the literature and grading the strength of available evidence. The process began by assembling a guideline development group of volunteers including orthopaedic surgeons, trainees, physiotherapists, rheumatologists, radiologists and patients. Virtual meetings were organised to set out explicit PICO questions, including specification of all important outcomes (including patient reported tennis elbow evaluation (PRTEE) as an important primary outcome) to determine the clinical effectiveness of common treatment options for LET compared with no treatment or placebo. Clinical librarian searched (date 31 April 2022) for available systematic reviews and randomised controlled trials reviewing the management of the LET January 2011 onwards and evidence was collected and summarized using explicit GRADE criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations were characterized as strong or weak (alternative terms conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of alternative management options. This informative summary provides the quality of available evidence for the management of LET.

Structural-Based Virtual Screening of FDA-Approved Drugs Repository for NSP16 Inhibitors, Essential for SARS-COV-2 Invasion Into Host Cells: Elucidation From MM/PBSA Calculation.

NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.

A Novel Inhibitor of DKK1/LRP6 Interactions Against the Alzheimer Disease: An Insilco Approach.

The activation of the Wnt signaling pathway is implicated in a neuroprotective mechanism against the Alzheimer disease. When this pathway is blocked, it activates GSK3 beta, leading to tau hyperphosphorylation and the apoptosis of neurons. Dickkopf-related protein 1 (DKK1) is a protein that competes with the Wnt ligand for the low-density lipoprotein receptor-related protein 6 (LRP6) receptor's binding, interrupting the Wnt-induced Fzd-Wnt-LRP6 complex. This counteracts Wnt's neuroprotective effect and contributes to the progression of the Alzheimer disease. The aim of this study was to use in silico approach to develop new agents that can combat the Alzheimer disease by targeting the interaction between DKK1 and LRP6. To achieve this, we conducted a virtual screening (Vsw) of the Asinex-CNS database library (n = 54 513) compounds against a generated grid in LRP6 protein. From this screening, we selected 6 compounds based on their docking score and performed molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations on the selected ligands. Next, we evaluated the Absorption, Distribution, Metabolism, and Excretion (ADME) results of the 6 screened compounds using the Quick prop module of Schrödinger. We then employed several computational techniques, including PCA (Principal Component Analysis), DCCM (Dynamic Cross-Correlation Map), molecular dynamics simulation, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)-based negative binding free energy (BFE) calculation, to further analyze the compounds. Our extensive computational analysis resulted in the identification of 3 potential hits, LAS 29757582, LAS 29984441, and LAS 29757942. These compounds were found to block the interaction of DKK1 with LRP6 (A and B interface) protein, and their potential as therapeutic agents was supported by negative BFE calculation. Therefore, these compounds show potential as possible therapeutic agents for treating the Alzheimer disease through targeting the interaction between DKK1 and LRP6.

Physiotherapy management of atraumatic anterior sternoclavicular joint instability: A prospective case series.

Background: Atraumatic sternoclavicular joint (SCJ) instability is rare. Long-term outcomes are presented for patients managed with physiotherapy. A standardised method of assessment and treatment with a structured physiotherapy programme is also presented. Methods: Long-term outcome was analysed in this prospectively collected series (2011-2019) of patients who were assigned to a structured physiotherapy programme for atraumatic SCJ instability. Outcome-measures (subjective SCJ grading of joint stability (SSGS score), Oxford shoulder instability score (OSIS adapted for SCJ) and visual analogue scale (VAS) for pain) were collected at discharge and long-term follow up. Results: 26 patients (29 SCJ's) responded (return rate 81%). Mean follow-up was 5.1 years (range 0.9-8.3 years). 17/26 patients were hyperlax. 93% (27/29) of SCJs achieved a stable joint on SSGS score. Mean OSIS score at long-term follow up was 33.4 (range 3-48) and VAS 2.7 (range 0-9). 95% who were compliant with physiotherapy had a stable SCJ (mean OSIS 37.8 (SD 7.3) and VAS 1.6 (SD 2.1)). Those non-compliant, 90% were stable but had lower function (mean OSIS 25 (SD 14, p = 0.02) and more pain, VAS 4.9 (SD 2.9, p = 0.006). Conclusion: The structured physiotherapy programme is highly effective in treating patients with atraumatic SCJ instability. Compliance was essential in ensuring better outcomes.

Designing the 5HT2BR structure and its modulation as a therapeutic target for repurposing approach in drug-resistant epilepsy.

The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (-53.44 kcal/mol) and Methylergonovine (-40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10-8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10-8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207-214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (-89.21 kcal/mol) than Methylergonovine (-63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy.

Investigating the novel-binding site of RPA2 on Menin and predicting the effect of point mutation of Menin through protein-protein interactions.

Protein-protein interactions (PPIs) play a critical role in all biological processes. Menin is tumor suppressor protein, mutated in multiple endocrine neoplasia type 1 syndrome and has been shown to interact with multiple transcription factors including (RPA2) subunit of replication protein A (RPA). RPA2, heterotrimeric protein required for DNA repair, recombination and replication. However, it's still remains unclear the specific amino acid residues that have been involved in Menin-RPA2 interaction. Thus, accurately predicting the specific amino acid involved in interaction and effects of MEN1 mutations on biological systems is of great interests. The experimental approaches for identifying amino acids in menin-RPA2 interactions are expensive, time-consuming, and challenging. This study leverages computational tools, free energy decomposition and configurational entropy scheme to annotate the menin-RPA2 interaction and effect on menin point mutation, thereby proposing a viable model of menin-RPA2 interaction. The menin-RPA2 interaction pattern was calculated on the basis of different 3D structures of menin and RPA2 complexes, constructed using homology modeling and docking strategy, generating three best-fit models: Model 8 (- 74.89 kJ/mol), Model 28 (- 92.04 kJ/mol) and Model 9 (- 100.4 kJ/mol). The molecular dynamic (MD) was performed for 200 ns and binding free energies and energy decomposition analysis were calculated using Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) in GROMACS. From binding free energy change, model 8 of Menin-RPA2 exhibited most negative binding energy of - 205.624 kJ/mol, followed by model 28 of Menin-RPA2 with - 177.382 kJ/mol. After S606F point mutation in Menin, increase of BFE (ΔGbind) by - 34.09 kJ/mol in Model 8 of mutant Menin-RPA2 occurs. Interestingly, we found a significant reduction of BFE (ΔGbind) and configurational entropy by - 97.54 kJ/mol and - 2618 kJ/mol in mutant model 28 as compared the o wild type. Collectively, this is the first study to highlight the configurational entropy of protein-protein interactions thereby strengthening the prediction of two significant important interaction sites in menin for the binding of RPA2. These predicted sites could be vulnerable for structural alternation in terms of binding free energy and configurational entropy after missense mutation in menin.

Medial Ulnar Collateral Ligament Repair With Augmentation: A Systematic Review and Meta-analysis of Preclinical Studies.

Background: Reconstruction is the gold standard treatment for medial ulnar collateral ligament (MUCL) injuries. However, recent studies show a successful and renewed interest in direct suture repair, particularly in young athletes. Repair augmentation with a suture tape may provide greater stability, enabling healing of the MUCL while protecting the repair at higher valgus loads. Purpose: To perform a systematic review and meta-analysis on whether MUCL repair with augmentation provides a similar biomechanical profile to the traditional MUCL reconstruction. Study Design: Systematic review. Methods: The Cochrane Controlled Register of Trials, PubMed, Medline, and Embase were used to perform a systematic review and meta-analysis using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria with the following search terms: ("ulnar collateral ligament" OR "medial ulnar collateral ligament") AND ("internal brace" OR "augmentation" OR "suture tape"). Data pertaining to certain biomechanical properties (gap formation, failure to torque [ultimate load to failure], stiffness, degree of valgus opening, and modes of failure) were extracted. The pooled outcome data were analyzed by random- and fixed-effects models. A total of 203 abstracts were identified through the aforementioned databases. Results: After abstract and full-text screening, 6 biomechanical studies were included. All were on cadaveric elbows, with 53 repairs with augmentation and 53 reconstructions compared. There were no differences between the 2 in regard to ultimate load to failure (standard mean difference [SMD], -0.34 N·m; 95% CI, -1.36 to 0.68; P = .51) and rotational stiffness (SMD, 0.26; 95% CI, -1.14 to 1.66; P = .72). Despite a trend in resistance to gapping with augmented repair, this was not significant (SMD, -0.53; 95% CI, -1.08 to 0.01; P = .06). Augmented repairs were more likely to fail by pullout or at the suture-tendon/anchor-suture interface (odds ratio [OR], 12.19; 95% CI, 4.17 to 35.62; P < .00001), while failure by fracture was more common with reconstruction (OR, 5.75; 95% CI, 2.07 to 15.99; P = .0008). Conclusion: MUCL augmented repair establishes the required time-zero structural properties without the need for a tendon graft. However, future clinical studies are necessary to determine its true effectiveness as well as its success at higher levels of professional sport.

Towards Novel HIV-1 Serodiagnostic Tests without Vaccine-Induced Seroreactivity.

Vaccine-induced seroreactivity/positivity (VISR/P) poses a significant and common challenge to HIV vaccine implementation, as up to 95% of vaccine recipients may be misclassified as having HIV infection by current HIV screening and confirmatory serological assays. We investigated whether internal HIV proteins could be used to overcome VISR and discovered a set of 4 antigens (gp41 endodomain, p31 integrase, p17 matrix protein, and Nef) that are recognized by antibodies produced in individuals with HIV infection but not in vaccinated individuals. When evaluated in a multiplex double-antigen bridging ELISA, this antigen combination had specificities of 98.1% prevaccination and 97.1% postvaccination, demonstrating the assay is minimally impacted by vaccine-induced antibodies. The sensitivity was 98.5%, further increasing to 99.7% when p24 antigen testing was included. Results were similar across HIV-1 clades. Although more technical advancements will be desired, this research provides the groundwork for the development of new fourth-generation HIV tests unaffected by VISR. IMPORTANCE While the detection of HIV infection is accomplished by several methods, the most common are serological tests that detect host antibodies produced in response to viral infection. However, the use of current serological tests may present a significant challenge to the adoption of an HIV vaccine in the future because the antibodies to HIV antigens detected in currently available tests also tend to be included as antigens in the HIV vaccines in development. The use of these serological tests may thus result in the misclassification of vaccinated HIV-negative individuals, which can have potential for significant harms for individuals and could prevent the widespread adoption and implementation of HIV vaccines. Our study aimed to identify and evaluate target antigens for inclusion in new serological tests that can be used to identify HIV infections without interference from vaccine-induced antibodies but also fit within existing platforms for HIV diagnostics.

Use of patient reported experience measure and patient reported outcome measures to evaluate differences in surgical or non-surgical management of humeral shaft fractures.

Background: The aim of this study was to evaluate the use of patient reported experience measures (PREMs) in humeral shaft fractures managed with or without surgery against patient reported outcome measures (PROMs). Methods: Adult patients treated for a humeral shaft fracture between June 2015 and August 2017 were included in non-surgery and surgery (early and late surgery) groups. The PREM questionnaire was based on patient and clinician feedback obtained during focus groups and was posted to patients. PROMs included the short form-12 (SF-12) and visual analogue scale (VAS) for pain, stiffness, function and satisfaction. Results: Eighty-one patients responded, 54 patients were treated in a brace and 27 with surgery (13 early, 14 late). There was moderate positive correlation between PREM and VAS satisfaction and function and moderate negative correlation with VAS pain and stiffness. There was also moderate positive correlation between PREM and SF-12 mental and weak positive correlation with SF-12 physical. The late surgery group had poorer PREMs (expectations, p = 0.002 and friends & family test, p = 0.0001) and PROMs (VAS satisfaction, p = 0.005) compared to the early surgery group. Conclusions: PREMs can be used in conjunction with PROMs to improve the patient's quality of care and as a means of identifying, at an early stage, those patients not doing well and to offer surgery.