Targeted epiphysiodesis using needle arthroscopy.

Epiphysiodesis is performed to either temporarily or permanently close the physis. It is considered in the management of angular deformities or limb length discrepancies. There are various surgical techniques that have been described. The gold-standard remains the mechanical removal of the physis using drills, burrs, and curettes. This requires intraoperative imaging to guide surgery and invariably leads to the mechanical removal of healthy cancellous bone as well as physeal cartilage. We report on a case of 'targeted epiphysiodesis' using needle arthroscopy. In this technique, radiation exposure and unnecessary bone loss is minimal. Epiphysiodesis is achieved under direct vision using a 1.9 mm needle arthroscope with a successful outcome and no surgical complications noted.

Recent advances in materials and manufacturing of implantable devices for continuous health monitoring.

Implantable devices are vital in healthcare, enabling continuous monitoring, early disease detection, informed decision-making, enhanced outcomes, cost reduction, and chronic condition management. These devices provide real-time data, allowing proactive healthcare interventions, and contribute to overall improvements in patient care and quality of life. The success of implantable devices relies on the careful selection of materials and manufacturing methods. Recent materials research and manufacturing advancements have yielded implantable devices with enhanced biocompatibility, reliability, and functionality, benefiting human healthcare. This paper provides a comprehensive overview of the latest developments in implantable medical devices, emphasizing the importance of material selection and manufacturing methods, including biocompatibility, self-healing capabilities, corrosion resistance, mechanical properties, and conductivity. It explores various manufacturing techniques such as microfabrication, 3D printing, laser micromachining, electrospinning, screen printing, inkjet printing, and nanofabrication. The paper also discusses challenges and limitations in the field, including biocompatibility concerns, privacy and data security issues, and regulatory hurdles for implantable devices.

Nascent adhesions shorten the period of lamellipodium protrusion through the Brownian ratchet mechanism.

Directional cell migration is driven by the conversion of oscillating edge motion into lasting periods of leading edge protrusion. Actin polymerization against the membrane and adhesions control edge motion, but the exact mechanisms that determine protrusion period remain elusive. We addressed this by developing a computational model in which polymerization of actin filaments against a deformable membrane and variable adhesion dynamics support edge motion. Consistent with previous reports, our model showed that actin polymerization and adhesion lifetime power protrusion velocity. However, increasing adhesion lifetime decreased the protrusion period. Measurements of adhesion lifetime and edge motion in migrating cells confirmed that adhesion lifetime is associated with and promotes protrusion velocity, but decreased duration. Our model showed that adhesions' control of protrusion persistence originates from the Brownian ratchet mechanism for actin filament polymerization. With longer adhesion lifetime or increased-adhesion density, the proportion of actin filaments tethered to the substrate increased, maintaining filaments against the cell membrane. The reduced filament-membrane distance generated pushing force for high edge velocity, but limited further polymerization needed for protrusion duration. We propose a mechanism for cell edge protrusion in which adhesion strength regulates actin filament polymerization to control the periods of leading edge protrusion.

Orthopaedic Eponyms: A Tool of the Past.

Eponyms are commonplace in the medical vernacular, however, their use has become increasingly controversial amongst clinicians. Whilst some view them as an honour bestowed on those whose achievements deserve recognition, others see them as thwarted with problems due to confusion, imprecision and unwittingly applauding controversial figures. Nevertheless, the history and culture retained within eponyms define modern-day medicine. To identify current trends in understanding of eponyms, we presented a questionnaire of orthopaedic eponyms and their associated imaging to unspecialised trainees, specialist orthopaedic trainees, and qualified consultants. Eponymous terms were poorly understood at all levels of experience, with- third and fourth-year Orthopaedic trainees (specialist trainee years five and six (ST5/ST6)) being outperformed (22.3%) by non-specialist postgraduate doctors with two or more years of experience (foundation year two (F2) and core surgery year two (CT2)) (29.3%). Based on these trends we present a further narrative review of the challenges eponyms present, whilst justifying their continued use to acknowledge the origins of our discipline, from the favourable to shameful.

A Community Health Worker-Based Intervention on Anthropometric Outcomes of Children Aged 3 to 21 Months in Urban Pakistan, 2019-2021.

Objectives. To evaluate the impact of a community health worker-based "in-home growth monitoring with counseling" (IHGMC) intervention on anthropometric outcomes in Pakistan, where 38% of children younger than 5 years are stunted. Methods. We used an individual, single-blind, step-wedge randomized controlled trial and a pure control group recruited at endline. We based the analysis on an intention-to-treat estimation using the coarsened exact matching (CEM) method for sample selection among treatments and the control. We conducted the baseline in July 2019 and completed endline in September-October 2021. We recruited 1639 households (treated: 1188; control: 451) with children aged 3 to 21 months who were residing in an urban informal settlement area. The CEM sample used for analysis numbered 1046 (treated: 636; control: 410). The intervention continued for 6 months. Results. Compared with the control group, the height-for-age z-score in the IHGMC group increased by 0.58 SD (95% confidence interval [CI] = 0.33, 0.83; P = .001) and the weight-for-age z-score by 0.43 SD (95% CI = 0.20, 0.67; P < .01), measured at endline. Conclusions. IHGMC substantially improved child anthropometric outcomes in disadvantaged localities, and this impact persisted during the COVID-19 pandemic. Trial Registration. AER-RCT registry (AEARCTR-0003248). (Am J Public Health. 2023;113(1):105-114. https://doi.org/10.2105/AJPH.2022.307111).

ERK signaling for cell migration and invasion.

The RAS - Extracellular signal-regulated kinase (RAS-ERK) pathway plays a conserved role in promoting cell migration and invasion. Growth factors, adhesion, and oncogenes activate ERK. While historically studied with respect to its control of cell proliferation and differentiation, the signaling pattern and effectors specific for cell migration are now coming to light. New advances in pathway probes have revealed how steady-state ERK activity fluctuates within individual cells and propagates to neighboring cells. We review new findings on the different modes of ERK pathway stimulation and how an increased baseline level of activity promotes single cell and collective migration and invasion. We discuss how ERK drives actin polymerization and adhesion turnover for edge protrusion and how cell contraction stimulates cell movement and ERK activity waves in epithelial sheets. With the steady development of new biosensors for monitoring spatial and temporal ERK activity, determining how cells individually interpret the multiple in vivo signals to ERK is within reach.

Open Reduction and Internal Fixation of a Calcaneal Anterior Process Fracture Using a Locking Plate.

Fractures involving the anterior process of the calcaneus (APC) are rare, underdiagnosed, and carry a significant increase in morbidity if not identified acutely. Identifying patients with intra-articular fracture extension is crucial as they may benefit from surgical fixation to reduce the risk of morbidity and post-traumatic osteoarthritis. There are no specific guidelines in the United Kingdom regarding the management of these fractures, and there is little evidence regarding optimal management, mainly limited to case reports and small sample observational trials. Previous reports of surgical intervention have described excision of fragments or fixation using single cancellous screws. A 55-year-old man fell from a height of 2 metres, sustaining an APC fracture extending into the calcaneocuboid joint. This was identified on plain radiographs following a virtual fracture clinic referral from the emergency department and further investigated with computed tomography scanning. He underwent open reduction and internal fixation with a locking T-plate and screws three weeks post-injury to restore congruence of his articular surface. Following a period of non-weight-bearing and progressive physiotherapy, he reported an excellent functional outcome six months post-operatively, measured by the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score of 90%. In the absence of specific guidelines for these fractures, this case provides an example of good initial functional outcomes following surgical fixation using a locking plate and screws, the first such fixation of an APC fracture described in the literature. This case can also be seen as a useful reminder of the need for an index of clinical suspicion for these injuries, given that up to 40% may be missed in the emergency department. While now fairly widespread, not all hospitals will have a virtual fracture clinic system in place, meaning emergency department practitioners must be wary of these injuries before discharging patients with suspicious histories and examination findings with no follow-up. Examination techniques that may help differentiate APC fractures from ankle sprains are discussed to provide clinicians with evidence to support a suspicion of these injuries in the emergency department.

Shoulder examination: a systematic approach.

The shoulder is a complex joint with static and dynamic stabilising structures working synchronously. These allow a full range of movement while preserving stability of the joint. Patients may present with pain, stiffness, weakness, deformity or instability. The authors suggest a systematic examination sequence to ensure that important pathology is not overlooked. Adopting this approach allows common pathologies, including tears of the rotator cuff, impingement and tendinopathy, to be easily identified. This shoulder examination sequence may be used by all healthcare professionals and can also act as a revision aid for those undergoing exams in this field, at different levels of training.

Subtractive proteomics approach to Unravel the druggable proteins of the emerging pathogen Waddlia chondrophila and drug repositioning on its MurB protein.

Waddlia chondrophila is an emerging pathogen that has been implicated in numerous unpropitious pregnancy events in humans and ruminants. Taking into account its association with abortigenic events, possible modes of transmission, and future risk, immediate clinical measures are required to prevent widespread damage caused by this organism and hence this study. Here, a subtractive proteomics approach was employed to identify druggable proteins of W. chondrophila. Considering the essential genes, antibiotic resistance proteins, and virulence factors, 676 unique important proteins were initially identified for this bacterium. Afterward, NCBI BLASTp performed against human proteome identified 223 proteins that were further pushed into KEGG Automatic Annotation Server (KAAS) for automatic annotation. Using the information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database 14 Waddlia specific metabolic pathways were identified with respect to humans. Analyzing the data from KAAS and KEGG databases, forty-eight metabolic pathway-dependent, and seventy metabolic pathway independent proteins were identified. Standalone BLAST search against DrugBank FDA approved drug targets revealed eight proteins that are finally considered druggable proteins. Prediction of three-dimensional structures was done for the eight proteins through homology modeling and the Ramachandran plot model showed six models as a valid prediction. Finally, virtual screening against MurB protein was performed using FDA approved drugs to employ the drug repositioning strategy. Three drugs showed promising docking results that can be used for therapeutic purposes against W. chondrophila following the clinical validation of the study.

Antiviral Peptides as Promising Therapeutics against SARS-CoV-2.

Over 50 peptides, which were known to inhibit SARS-CoV-1, were computationally screened against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. Based on the binding affinity and interaction, 15 peptides were selected, which showed higher affinity compared to the α-helix of the human ACE2 receptor. Molecular dynamics simulation demonstrated that two peptides, S2P25 and S2P26, were the most promising candidates, which could potentially block the entry of SARS-CoV-2. Tyr489 and Tyr505 residues present in the "finger-like" projections of the RBD were found to be critical for peptide interaction. Hydrogen bonding and hydrophobic interactions played important roles in prompting peptide-protein binding and interaction. Structure-activity relationship indicated that peptides containing aromatic (Tyr and Phe), nonpolar (Pro, Gly, Leu, and Ala), and polar (Asn, Gln, and Cys) residues were the most significant contributors. These findings can facilitate the rational design of selective peptide inhibitors targeting the spike protein of SARS-CoV-2.

Predicting and Designing Epitope Ensemble Vaccines against HTLV-1.

The infection mechanism and pathogenicity of Human T-lymphotropic virus 1 (HTLV-1) are ambiguously known for hundreds of years. Our knowledge about this virus is recently emerging. The purpose of the study is to design a vaccine targeting the envelope glycoprotein, GP62, an outer membrane protein of HTLV-1 that has an increased number of epitope binding sites. Data collection, clustering and multiple sequence alignment of HTLV-1 glycoprotein B, variability analysis of envelope Glycoprotein GP62 of HTLV-1, population protection coverage, HLA-epitope binding prediction, and B-cell epitope prediction were performed to predict an effective vaccine. Among all the predicted peptides, ALQTGITLV and VPSSSTPL epitopes interact with three MHC alleles. The summative population protection coverage worldwide by these epitopes as vaccine candidates was found nearly 70%. The docking analysis revealed that ALQTGITLV and VPSSSTPL epitopes interact strongly with the epitope-binding groove of HLA-A*02:03, and HLA-B*35:01, respectively, as this HLA molecule was found common with which every predicted epitope interacts. Molecular dynamics simulations of the docked complexes show they form stable complexes. So, these potential epitopes might pave the way for vaccine development against HTLV-1.

Halogenated derivatives of methotrexate as human dihydrofolate reductase inhibitors in cancer chemotherapy.

Methotrexate is a widely used anti-metabolite in cancer chemotherapy. A series of halogenated drugs is designed from Methotrexate to assess their interactions with human dihydrofolate reductase. The aim of this study is to evaluate the performance of the modified drugs compared to the parent Methotrexate. Density Functional Theory is employed to optimize these drugs. Molecular docking calculation of these optimized drugs against dihydrofolate reductase is performed to find out binding affinity. In addition, molecular dynamics simulation is considered for the complexes of best two modified drugs with their receptors. Modifications by the halogens show significant changes in the charge distribution, dipole moment, thermodynamic stability, enthalpy and free energy. The highest binding affinity value (-36.401 KJ/mol) was obtained for M14. Hybrid quantum mechanics/molecular mechanics calculation shows a binding energy of -255.140 KJ/mol. Modified drugs have significant hydrogen and non-covalent bonding interactions with amino acids of the receptor. Molecular dynamics simulation disclosed that the root-mean-square-deviation of the alpha carbon associated with M6-1KMV and M14-1KMV complexes is 2.367 Å and 2.622 Å, respectively. Moreover, the interactions between modified drugs and receptor are mostly persevered in 25 nanosecond molecular dynamics simulation. Ensemble-based docking also confirmed that modified drugs show strong non-bonding interactions with different crystallographic and molecular dynamics based conformers. The best scored drugs show considerable pharmacokinetic properties. Modified derivatives M5, M6, M8, M10, M13 and M14 show the better binding affinity and a good number of hydrogen and other non-bonding interactions with the target protein which are similar to other anticancer drugs.Communicated by Ramaswamy H. Sarma.

Prediction of Deleterious Non-synonymous SNPs of Human STK11 Gene by Combining Algorithms, Molecular Docking, and Molecular Dynamics Simulation.

Serine-threonine kinase11 (STK11) is a tumor suppressor gene which plays a key role in regulating cell growth and apoptosis. It is widely known as a multitasking kinase and engaged in cell polarity, cell cycle arrest, chromatin remodeling, energy metabolism, and Wnt signaling. The substitutions of single amino acids in highly conserved regions of the STK11 protein are associated with Peutz-Jeghers syndrome (PJS), which is an autosomal dominant inherited disorder. The abnormal function of the STK11 protein is still not well understood. In this study, we classified disease susceptible single nucleotide polymorphisms (SNPs) in STK11 by using different computational algorithms. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking and molecular dynamics analysis. Our results show that W239R and W308C variants are likely to be highly deleterious mutations found in the catalytic kinase domain, which may destabilize structure and disrupt the activation of the STK11 protein as well as reduce its catalytic efficiency. The W239R mutant is likely to have a greater impact on destabilizing the protein structure compared to the W308C mutant. In conclusion, these mutants can help to further realize the large pool of disease susceptibilities linked with catalytic kinase domain activation of STK11 and assist to develop an effective drug for associated diseases.

Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations.

Molecular recognition has central role on the development of rational drug design. Binding affinity and interactions are two key components which aid to understand the molecular recognition in drug-receptor complex and crucial for structure-based drug design in medicinal chemistry. Herein, we report the binding affinity and the nonbonding interactions of azelaic acid and related compounds with the receptor DNA polymerase I (2KFN). Quantum mechanical calculation was employed to optimize the modified drugs using B3LYP/6-31G(d,p) level of theory. Charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and free energy of these optimized drugs are also explored to evaluate how modifications impact the drug properties. Molecular docking calculation was performed to evaluate the binding affinity and nonbonding interactions between designed molecules and the receptor protein. We notice that all modified drugs are thermodynamically more stable and some of them are more chemically reactive than the unmodified drug. Promise in enhancing hydrogen bonds is found in case of fluorine-directed modifications as well as in the addition of trifluoroacetyl group. Fluorine participates in forming fluorine bonds and also stimulates alkyl, pi-alkyl interactions in some drugs. Designed drugs revealed increased binding affinity toward 2KFN. A1, A2 and A3 showed binding affinities of -8.7, -8.6 and -7.9 kcal/mol, respectively against 2KFN compared to the binding affinity -6.7 kcal/mol of the parent drug. Significant interactions observed between the drugs and Thr358 and Asp355 residues of 2KFN. Moreover, designed drugs demonstrated improved pharmacokinetic properties. This study disclosed that 9-octadecenoic acid and drugs containing trifluoroacetyl and trifluoromethyl groups are the best 2KFN inhibitors. Overall, these results can be useful for the design of new potential candidates against DNA polymerase I.

Multiple receptor conformers based molecular docking study of fluorine enhanced ethionamide with mycobacterium enoyl ACP reductase (InhA).

A major limitation in current molecular docking method is that of failure to account for receptor flexibility. Herein we report multiple receptor conformers based molecular docking as a practical alternative to account for the receptor flexibility. Multiple (forty) conformers of Mycobacterium Enoyl ACP Reductase (InhA) are generated from Molecular Dynamics simulation and twenty crystallographic structures of InhA bound to different inhibitors are obtained from the Protein Data Bank. Fluorine directed modifications are performed to currently available anti-tuberculosis drug ethionamide. The modified drugs are optimized using B3LYP 6-31G (d,p) level of theory. Dipole moment, frontier orbital gap and thermodynamical properties such as electronic energy, enthalpy and Gibbs free energy of these optimized drugs are investigated. These drugs are subsequently docked against the conformers of InhA. Molecular docking against multiple InhA conformations show variation in ligand binding affinity and suggest that Ser94, Gly96, Lys165 and Ile194 amino acids play critical role on strong drug-InhA interaction. Modified drug N1 showed greater binding affinity compared to EN in most conformations. Structure of PDB ID: 2NSD and snapshot conformer at 5.5ns show most favorable binding with N1 compared to other conformers. Fluorine participates in forming fluorine bonds and contributes significantly in increasing binding affinity. Our study reveal that addition of trifluoromethyl group explicitly shows promise in improving thermodynamic properties and in enhancing hydrogen bonding and non-bonded interactions. Molecular dynamics (MD) simulation show that EN and N1 remained in the binding pocket similar to the docked pose of EN-InhA and E1-InhA complexes and also suggested that InhA binds to its inhibitor in inhibitor-induced folding manner. ADMET calculations predict modified drugs to have improved pharmacokinetic properties. Our study concludes that multiple receptor conformers based molecular docking can be an alternative to study the effect of receptor flexibility in ligand binding and fluorine directed modifications can improve drug efficacy.

The Epidemiology of Adult Distal Femoral Shaft Fractures in a Central London Major Trauma Centre Over Five Years.

BACKGROUND: Distal femoral fractures account for 3-6% of adult femoral fractures and 0.4% of all fractures and are associated with significant morbidity and mortality rates. As countries develop inter-hospital trauma networks and adapt healthcare policy for an aging population there is growing importance for research within this field. METHODS: Hospital coding and registry records at the central London Major Trauma Center identified 219 patients with distal femoral shaft fractures that occurred between December 2010 and January 2016. CT-Scans were reviewed resulting in exclusion of 73 inappropriately coded, 10 pediatric and 12 periprosthetic cases. Demographics, mechanism of injury, AO/OTA fracture classification and management were analyzed for the remaining 124 patients with 125 fractures. Mann Whitney U and Chi Squared tests were used during analyses. RESULTS: The cases show bimodal distribution with younger patients being male (median age 65.6) compared to female (median age 71). Injury caused through high-energy mechanisms were more common in men (70.5%) whilst women sustained injuries mainly from low-energy mechanisms (82.7%) (p<0.0001). Majority of fractures were 33-A (52.0%) followed by 33-B (30.4%) and 33-C (17.6%). Ninety-two (73.6%) underwent operative management. The most common operation was locking plates (64.1%) followed by intramedullary nailing (19.6%). INTERPRETATION: The epidemiology of a rare fracture pattern with variable degrees of complexity is described. A significant correlation between biological sex and mechanism of injury was identified. The fixation technique favored was multidirectional locking plates. Technical requirements for fixation and low prevalence of 33-C fractures warrant consideration of locating treatment at centers with high caseloads and experience.

Trends and determinants of inequities in childhood stunting in Bangladesh from 1996/7 to 2014.

BACKGROUND: We explore long-term trends and determinants of socioeconomic inequities in chronic childhood undernutrition measured by stunting among under-five children in Bangladesh. Given that one in three children remain stunted in Bangladesh, the socioeconomic mapping of stunting prevalence may be critical in designing public policies and interventions to eradicate childhood undernutrition. METHODS: Six rounds of Bangladesh Demographic and Health Survey data are utilized, spanning the period 1996/97 to 2014. Using recognized measures of absolute and relative inequality (namely, absolute and relative difference, concentration curve and index), we quantify trends, and decompose changes in the concentration index to identify factors that best explain observed dynamics. RESULTS: Despite remarkable improvements in average nutritional status over the last two decades, socio-economic inequalities have persisted, and according to some measures, even worsened. For example, expressed as rate-ratios, the relative inequality in under-five stunting increased by 56% and the concentration index more than doubled between 1996/97 and 2014. Decomposition analyses find that wealth and maternal factors such as mothers' schooling and short stature are major contributors to observed socio-economic inequalities in child undernutrition and their changes over time. CONCLUSIONS: Reflecting on recent success around socioeconomic and gender equity in child mortality, and the weak legacy of nutrition policy in Bangladesh, we suggest that nutrition programming energies be focused specifically on the most disadvantaged and applied at scale to close socioeconomic gaps in stunting prevalence.