Autologous versus synthetic midurethral transobturator sling: A systematic review and meta-analysis of outcomes.

INTRODUCTION: There have been concerns around the use of synthetic mesh for stress urinary incontinence (SUI) surgery with a renewed interest in the use of autologous tissues. Recently, an autologous transobturator sling (aTOT) has been described, but the comparative data with synthetic transobturator sling (sTOT) is limited. The objective of this systematic review and meta-analysis was to assess the outcome of aTOT and compare it with sTOT. METHODS: A systematic search of PubMed, Scopus, and Web of Science databases was performed and all articles available up to December 31, 2023 were screened. Studies reporting on the outcomes of aTOT and those comparing aTOT with sTOT were included. This review was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Eleven studies evaluating 323 patients that met the criteria were included in the final analysis, of which 6 were single arm (155 patients) and 5 were comparative. In single-arm studies, the pooled success rate, defined as negative cough stress test at 12 months follow-up was 96.8%, 3.8% had postoperative urinary retention, 6.1% had graft site-related complications and 7.6% required additional intervention for persistent SUI. The overall complication rate was 20.6% and there were no Clavien III-V complications. aTOT had similar success and complication rates when compared with sTOT but had a significantly longer operative time (weighted mean difference: 22.35 min, p < 0.00001) and superior sexual function outcomes. CONCLUSIONS: aTOT, at short-term follow-up (12 months), has similar efficacy and complication rates when compared to sTOT. However, given that the data is limited and not of very good quality, and the fact that long-term follow-up is not available, further studies are required to better define the role of aTOT in the management of female patients with SUI.

"Primary" bulbar urethral ischemic necrosis following pelvic fracture urethral injury: A rare surgical challenge.

Ischemic necrosis of the bulbar urethra in a patient with pelvic fracture urethral injury without a prior history of surgical intervention is extremely rare and results in long-segment obliterative strictures that are difficult to manage. Instead of the more traditional approach of vascular reconstruction followed by transpubic end-to-end urethroplasty, these patients are better managed by up-front urethroplasty with a tubed flap or as a staged procedure with grafting and tubularization. Herein, we report a case of primary bulbar urethral ischemic necrosis due to pelvic fracture managed with tubularized preputial flap (McAninch flap) urethroplasty.

Urodynamic assessment of detrusor function in the very acute phase of traumatic spinal cord injury: A prospective cohort study.

Introduction: The bladder is believed to be acontractile due to the phase of spinal shock and there is a lack of data on the detrusor function within the first few days after spinal cord injury (SCI). This study intended to assess the detrusor function with invasive urodynamics (UDS) during the first 15 days of SCI. Methods: This prospective observational study was carried out from January 2020 to June 2021 and consecutive stable patients older than 18 years of age who had a history of traumatic SCI within the past 15 days were screened for inclusion. For each patient, the International Standards for Neurological Classification of SCI Worksheet was filled. All patients underwent bedside invasive UDS within 15 days of injury. Results: There were a total of 41 patients with a mean age of 35 years. The thoracic cord was most commonly involved (46.3%) with Type A AISA grade being the most common (68.2%). The mean duration of injury at the time of UDS was 6 days. Abnormality in the filling phase could be identified in six patients. Three patients had neurogenic detrusor overactivity (NDO), with one having a high-pressure phasic NDO and one having a sustained NDO. Two patients had poor compliance and one had borderline poor compliance. None of the patients generated any detrusor pressure during voiding cystometry. Conclusions: In patients with SCI, 14.5% of the patients had abnormal findings during the filling phase on the UDS performed within 15 days of the injury. These findings are in stark contrast to the traditional understanding that the detrusor is acontractile during the early phase of the SCI and merit further evaluation.

Identification and mechanistic exploration of structural and conformational dynamics of NF-kB inhibitors: rationale insights from in silico and in vitro studies.

Increased expression of target genes that code for proinflammatory chemical mediators results from a series of intracellular cascades triggered by activation of dysregulated NF-κB signaling pathway. Dysfunctional NF-kB signaling amplifies and perpetuates autoimmune responses in inflammatory diseases, including psoriasis. This study aimed to identify therapeutically relevant NF-kB inhibitors and elucidate the mechanistic aspects behind NF-kB inhibition. After virtual screening and molecular docking, five hit NF-kB inhibitors opted, and their therapeutic efficacy was examined using cell-based assays in TNF-α stimulated human keratinocyte cells. To investigate the conformational changes of target protein and inhibitor-protein interaction mechanisms, molecular dynamics (MD) simulations, binding free energy calculations together with principal component (PC) analysis, dynamics cross-correlation matrix analysis (DCCM), free energy landscape (FEL) analysis and quantum mechanical calculations were carried out. Among identified NF-kB inhibitors, myricetin and hesperidin significantly scavenged intracellular ROS and inhibited NF-kB activation. Analysis of the MD simulation trajectories of ligand-protein complexes revealed that myricetin and hesperidin formed energetically stabilized complexes with the target protein and were able to lock NF-kB in a closed conformation. Myricetin and hesperidin binding to the target protein significantly impacted conformational changes and internal dynamics of amino acid residues in protein domains. Tyr57, Glu60, Lys144 and Asp239 residues majorly contributed to locking the NF-kB in a closed conformation. The combinatorial approach employing in silico tools integrated with cell-based approaches substantiated the binding mechanism and NF-kB active site inhibition by the lead molecule myricetin, which can be explored as a viable antipsoriatic drug candidate associated with dysregulated NF-kB.Communicated by Ramaswamy H. Sarma.

Miller-Fisher Syndrome Unveiled in the Presence of Cholangiocarcinoma.

Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome, characterized by ataxia, areflexia, ophthalmoplegia, and possible facial, swallowing and limb weakness alongside respiratory failure. Variations within MFS may include respiratory and limb weakness and Bickerstaff brainstem encephalitis (BBE), marked by altered consciousness, ataxia, ophthalmoparesis, and paradoxical hyperreflexia. MFS can emerge in both children and adults, often following bacterial or viral illness. While autoimmune-driven nerve damage occurs, most MFS patients recover within six months without specific treatment, with a low risk of lasting neurological deficits or relapses. Rarely fatal, MFS's co-occurrence with cholangiocarcinoma (CCA) presents unique management challenges. CCA, primarily affecting bile ducts, has a bleak prognosis; surgical resection offers limited cure potential due to late-stage detection and high recurrence rates. Advances in CCA's molecular understanding have led to novel diagnostic and therapeutic approaches, requiring a comprehensive interdisciplinary care approach for optimal MFS and CCA management outcomes. Herein, we present a 50-year-old male with a complex medical history who was admitted to the hospital due to abdominal discomfort, nausea, vomiting, and ascites. Imaging revealed pneumonia and secondary bacterial peritonitis. Later, he developed neurological symptoms, including weakness, gait abnormalities, and brainstem symptoms, leading to the diagnosis of MFS. Despite treatment efforts, his condition deteriorated, leading to acute liver failure and unexplained anasarca. N-acetyl cysteine was initiated for liver issues. Neurologically, he showed quadriparesis and areflexia. Intravenous immunoglobulin (IVIG) treatment improved his neurological symptoms but worsened gastrointestinal issues, including ileus and elevated CA19-9 levels, suggesting a potential carcinoma. A liver biopsy was performed. After IVIG treatment, he experienced widespread discomfort, emotional unresponsiveness, swallowing difficulties, and aspiration risk, ultimately leading to his demise.

Upper moiety vascular ureteropelvic junction obstruction in an incomplete duplex kidney: A variant of the Fraley's syndrome?

Although duplication of the collecting system is fairly common, ureteropelvic junction obstruction of the upper moiety in a patient with duplex system is rare, more so if the obstruction is extrinsic and vascular. Herein, we report a case of obstruction of the upper moiety infundibulum by a crossing vein, in a patient with partially duplex system who presented with flank pain and focal hydronephrosis of the superior calyx, a clinical presentation similar to that of Fraley's syndrome. The infundibulum was transected and transposed anterior to the crossing vessel.

Elucidating the zinc-binding proteome of Fusarium oxysporum f. sp. lycopersici with particular emphasis on zinc-binding effector proteins.

Fusarium oxysporum f. sp. lycopersici is a soil-borne phytopathogenic species which causes vascular wilt disease in the Solanum lycopersicum (tomato). Due to the continuous competition for zinc usage by Fusarium and its host during infection makes zinc-binding proteins a hotspot for focused investigation. Zinc-binding effector proteins are pivotal during the infection process, working in conjunction with other essential proteins crucial for its biological activities. This work aims at identifying and analysing zinc-binding proteins and zinc-binding proteins effector candidates of Fusarium. We have identified three hundred forty-six putative zinc-binding proteins; among these proteins, we got two hundred and thirty zinc-binding proteins effector candidates. The functional annotation, subcellular localization, and Gene Ontology analysis of these putative zinc-binding proteins revealed their probable role in wide range of cellular and biological processes such as metabolism, gene expression, gene expression regulation, protein biosynthesis, protein folding, cell signalling, DNA repair, and RNA processing. Sixteen proteins were found to be putatively secretory in nature. Eleven of these were putative zinc-binding protein effector candidates may be involved in pathogen-host interaction during infection. The information obtained here may enhance our understanding to design, screen, and apply the zinc-metal ion-based antifungal agents to protect the S. lycopersicum and control the vascular wilt caused by F. oxysporum.

GlucoKinaseDB: A comprehensive, curated resource of glucokinase modulators for clinical and molecular research.

Glucokinase (GK), an isoform of hexokinase expressed predominantly in liver, pancreas and hypothalamus is crucial to blood glucose management. It is a critical component of the glucose-sensing mechanism of the pancreatic islet cells and glycogen regulation in hepatocytes. GK modulators such as allosteric GKAs (glucokinase activators) and GK-GKRP (glucokinase regulatory protein) disruptors have found potential applications as safer antihyperglycemics. Recent studies have also demonstrated the potential of GK modulators as antiparasitic agents. Researchers targeting GK often undertake the time-consuming task of independently collecting and compiling modulator information due to the lack of any dedicated single-platform resource. Towards this, in the present study we demonstrate the design and development of GlucoKinaseDB (GKDB), a comprehensive, curated, online resource of GK modulators. GKDB contains experimentally derived structural and bioactivity information of 1723 modulators along with their detailed molecular descriptors. The web-interface is user-friendly with features such as in-browser visualization, advanced search queries, cross-links to other databases and original reference etc. The bioactivity and descriptor data can be downloaded in bulk (for entire database) or for individual modulators. The 3D structures are also downloadable in multiple formats. GKDB employs a PHP-based web design with Bootstrap styling and a MySQL database backend. GKDB can be utilized for clinical and molecular research via development of pharmacophore hypotheses, QSAR/QSPR models, predictive machine learning models etc. GKDB is freely accessible online at https://glucokinasedb.in.

Lead optimization, pharmacophore development and scaffold design of protein kinase CK2 inhibitors as potential COVID-19 therapeutics.

Therapeutic agents being designed against COVID-19 have targeted either the virus directly or the host cellular machinery. A particularly attractive host target is the ubiquitous and constitutively active serine-threonine kinase, Protein kinase CK2 (CK2). CK2 enhances viral protein synthesis by inhibiting the sequestration of host translational machinery as stress granules and assists in viral egression via association with the N-protein at filopodial protrusions of the infected cell. CK2 inhibitors such as Silmitasertib have been proposed as possible therapeutic candidates in COVID-19 infections. The present study aims to optimize Silmitasertib, develop pharmacophore models and design unique scaffolds to modulate CK2. The lead optimization phase involved the generation of compounds structurally similar to Silmitasertib via bioisostere replacement followed by a multi-stage docking approach to identify drug-like candidates. Molecular dynamics (MD) simulations were performed for two promising candidates (ZINC-43206125 and PC-57664175) to estimate their binding stability and interaction. Top scoring candidates from the lead optimization phase were utilized to build ligand-based pharmacophore models. These models were then merged with structure-based pharmacophores (e-pharmacophores) to build a hybrid hypothesis. This hybrid hypothesis was validated against a decoy set and used to screen a diverse kinase inhibitors library to identify favored chemical features in the retrieved actives. These chemical features include; an anion, an aromatic ring and an H-bond acceptor. Based on the knowledge of these features; de-novo scaffold design was carried out which identified phenindiones, carboxylated steroids, macrocycles and peptides as novel scaffolds with the potential to modulate CK2.Communicated by Ramaswamy H. Sarma.

Computational biology insights into genotype-clinical phenotype-protein phenotype relationships between novel SLC26A2 variants identified in inherited skeletal dysplasias.

BACKGROUND: Pathogenic variants in the transmembrane sulfate transporter protein SLC26A2 are associated with different phenotypes of inherited chondrodysplasias. As limited data is published from India, in this study we sought to elucidate the molecular basis of inherited chondrodysplasias in an Indian cohort. METHODS: Molecular screening of 32 fetuses with antenatally diagnosed lethal skeletal dysplasia was performed by next generation sequencing and Sanger sequencing. The genotype-protein phenotype characterization was done using computational biology techniques like homology modelling, stability and pathogenicity predictions. RESULTS: We identified five rare autosomal recessive SLC26A2 [NM_000112.4] variants, including three homozygous c.796dupA(p.Thr266Asnfs*12), c.1724delA(p.Lys575Serfs*10), and c.1375_1377dup(p.Val459dup) and two heterozygous variants (c.532C > T(p.Arg178*)) and (c.1382C > T(p.Ala461Val)) in compound heterozygous form in a total of four foetuses. Genotype-protein phenotype annotations highlighted that the clinically severe achondrogenesis 1B causative c.796dupA(p.Thr266Asnfs*12) and c.1724delA(p.Lys575Serfs*10)variants impact SLC26A2 protein structure by deletion of the protein core and transmembrane STAS domains, respectively. In clinically moderate atelosteogenesis type 2 phenotype, the c.1382C > T(p.Ala461Val) variant is predicted to distort alpha helix conformation and alter the bonding properties and free energy dynamics of transmembrane domains and the c.532C > T(p.Arg178*) variant results in loss of both core transmembrane and STAS domains of the SLC26A2 protein. The c.1375_1377dup(p.Val459dup) variant identified in clinically milder atelosteogenesis type II-diastrophic dysplasia spectrum lethal phenotype is predicted to decrease the Qualitative Model Energy Analysis (QMean), which affects major geometrical aspects of the SLC26A2 protein structure. CONCLUSION: We expand the spectrum of SLC26A2 related lethal chondrodysplasia and report three novel variants correlating clinical severity and protein phenotype within the lethal spectrum of this rare dysplasia. We demonstrate the relevance of structural characterization to aid novel variant reclassification to provide better prenatal management and reproductive options to families with lethal antenatal skeletal disorder.

Biochemical Correlation of Thyroid Dysfunction Among Patients Presenting With Polymorphic Light Eruption.

Objective The pathophysiology of polymorphic light eruption (PMLE) is uncertain; however, it is considered to commonly involve an autoimmunological mechanism. It is a common condition, usually affecting subjects staying at temperate latitudes, and presents with eruptions post-exposure to sunlight and artificial UVR (ultraviolet radiation), lasting from hours to, in rare cases, days of exposure. This present study aims to compare biochemical thyroid function tests in cases of PMLE.  Methodology The present case-control study was conducted with a total of 120 participants. Patients with polymorphic light eruption aged 18 years or above of either sex attending the dermatology outpatient department were included in the study. TSH (thyroid-stimulating hormone), T3 (triiodothyronine), and T4 (thyroxine) were analyzed among the participants. The data was recorded on a Microsoft Excel spreadsheet and analyzed using SPSS Statistics v. 21 (IBM Corp., Armonk, NY). The qualitative data was assessed in the form of numbers and percentages and the quantitative data was assessed using measures of central tendency such as mean and standard deviation. A chi-square test was applied to find out the association and their strength between the variables to validate the findings of the study. A p-value <0.05 was considered to be statistically significant. Results The TSH was elevated in 56 (93.3%) cases and two (3.3%) among the controls; T3 and T4 were low in 24 (40%) cases, and in seven (11.7%) among the controls. Conclusion PMLE usually has an autoimmune basis for its occurrence; similarly, thyroid disorders being themselves autoimmune in origin might lead to hypersensitivity reactions and generation of autoantibodies. We suggest that screening for thyroid should be conducted for all PMLE patients as they are at higher risk of developing thyroid disorders. The relationship between the two should be studied with a much larger cohort of participants to evaluate whether this is autoimmune-related or accidentally related.

Comparative Study of Postoperative Outcomes of Clavicle Midshaft Fracture Treated by Nailing vs. Plating.

Background A midshaft clavicle fracture is a prevalent form of injury of the upper extremity that affects one's quality of life. Several treatment modalities facilitate fixation of the displaced midshaft clavicle to decrease nonunion and malunion of the clavicle fracture. Still, numerous factors influence choosing an optimal surgical intervention. Thus, this study investigates the functional outcome of two standard fixation techniques, titanium elastic nails (TENs) and locking plates, as a prospective comparative study for surgical management of displaced midshaft clavicle fractures. Methods We performed closed/open reduction and internal fixation in 62 patients (40 male and 22 female) with TENs and locking plates, respectively, which were followed up at regular intervals following the surgery (at two, six, 12, 24, and 48 weeks). The surgical outcome was assessed both from functional and radiological standpoints. The influence of surgical fixation on functional outcome was evaluated based on the Constant-Murley score and the fracture recuperation based on union times. Results When compared to plate fixation, TENs had lesser union times. Still, there was no statistical difference in union time between the two groups. The functional assessment graded by Constant-Murley score had a similar distribution of scores between the two groups.With a follow-up of twelve months, the Constant-Murley scores between the groups were not statistically different. While the average score for plate fixation was slightly higher than that of TENs, the nonunion rate was found to be similar in both groups. Conclusion Surgical interventions using both TENs and plate fixation are suitable for managing clavicle midshaft fractures as they have a similar functional outcome. However, considering early recovery with minimal surgical complications, TENs can be a preferred treatment choice for managing displaced midshaft clavicle fractures.

A Solitary Enchondroma of the Great Toe in an Adolescent Male: A Case Report.

Solitary enchondromas are benign and usually asymptomatic. Enchondromas are a form of cartilage tumor and have a higher chance of converting into chondrosarcoma. It is difficult to obtain a valid risk estimate, as this requires histopathology and MRI reports. A 17-year-old male presented with swelling over the left great toe since six months, which was insidious in onset, gradually progressive, and associated with intermittent dull aching type of pain. Physical examination revealed bony hard swelling of size 3 x 2.5cm over the left great toe. X-ray was suggestive of lytic lesions, scalloping of the cortex, and whorl of calcification. After confirming the diagnosis through MRI and histopathological examination, the decision was taken to remove whole of the proximal phalanx along with the tumor. Gap was filled up with fibular strut graft. Solitary enchondromas that are aggressively increasing in size should be treated surgically. Bone gap (between the first metatarsal and distal phalanx) caused after removing the tumor can be filled with bone graft or cement depending on the condition of the cortex.

Assessment of Functional and Radiological Outcomes of Comminuted Intra-Articular Distal Radius Fracture Treated With Locking Compression Plate.

Background Distal radial fractures (DRFs) are a prevalent form of skeletal injuries that hinder a person from performing daily living activities. Although several treatment modalities have been established to manage DRF, an optimal intervention has not been identified for comminuted fractures. The use of locking compression plates (LCPs) is gaining popularity for fractures that cannot be anatomically reduced because they offer better stability and early recovery. Thus, this study aims to investigate the surgical outcome of comminuted intra-articular DRFs treated with LCPs. Methodology We performed open reduction and internal fixation in 30 patients (18 males and 12 females) with DRF and were followed up at regular intervals following the surgery (at three, six, twelve, and twenty-four weeks). The surgical outcome was assessed both from functional and radiological standpoints. The influence of LCP on functional outcome was evaluated based on the modified Mayo wrist score and the quality of reduction based on the Lindstrom criteria by observing volar tilt and radial inclination. Results For radiological outcome, there was no variation in tilt/inclination of more than two degrees even after three months, which was a satisfactory result. Moreover, patients of all age groups showed early range of motion and functional benefit from LCP treatment. After six months of treatment, the patients experienced no pain and were able to return to their pre-injury jobs with little difficulty. Range of motion, work status, and grip strength after six months showed improvement of 15%, 7.8%, and 56%, respectively, compared to immediate postoperative assessments at three weeks. Although the end outcome with any treatment modality may yield similar results, when using LCPs, most patients experienced early functional improvement nearly six months after surgery. Conclusions By offering a lower risk of complications and early functional mobility, LCPs tend to restore the articular architecture of the fractured joint that results in the desired range of motion, grip strength, improved pain management, and functional status. Thus, LCPs appear to be a better alternative for distal end radial fractures than other treatment modalities.

A Rare Case of Giant-Cell Tumor of Hand in a Young Male.

Giant-cell tumor (GCT) of the bone affecting the hand is a rare lesion that is usually diagnosed at an advanced stage and has a high rate of recurrence. In the current literature, GCT is described as a predominantly osteoclastogenic stromal cell tumor of mesenchymal origin. It is composed of three cell types: the neoplastic GCT stromal cells; mononuclear monocyte cells; and multinucleated giant cells. Clinical imaging is basic for the diagnosis of a GCT. This tumor within the hand tends to be less eccentric and most often central. GCT of metacarpals is noted to be a rare location, with the incidence being as low as 2%. GCT on hand as compared to other sites is locally more aggressive, grows faster, and has a higher recurrence rate. A 22-year-old male patient presented with swelling over the left hand for 7 months, spontaneous in onset, gradually progressive in size, and painfully restricting the joint movement, with no history of fall or trauma. On examination, diffuse swelling of size 5 × 5 × 3 cm was tender on palpation, restricting the movement at the 4th metacarpophalangeal joint. A plain radiograph followed by an MRI scan revealed a Campanacci's Grade III GCT of the 4th metacarpal. An open biopsy showed an expanded and lytic mass with areas of hemorrhage and necrosis. There were few mitotic figures and the tumor was diagnosed to be a GCT. On surgical resection, friable tumor tissue was noted over the region of the entire 4th metacarpal except for the base. The patient was managed by surgical intralesional excision of the mass, followed by Kirschner-wire fixation and reconstruction with synthetic bone graft. The excised tissue was sent for histopathological examination. The patient was followed up at regular intervals, with initial splinting, followed by wire removal at 6-week post-op, and with adequate physiotherapy, as tolerated by the patient. On a 3-month follow-up, the range of motion had returned to a functional level, with good uptake of graft, and no other complications. GCT of the hand is a rare presentation of the disease and requires meticulous workup, including a thorough clinical exam, hematological, radiological, and pathological workup. The various treatment modalities described in the literature for GCTs are curettage alone, curettage and bone graft, en-bloc resection, amputation, and resection with reconstruction, but curettage alone or curettage with bone graft is not effective even for GCTs of long bones and hand, too. Such a procedure creates a skeletal void and hence furthers the need for a challenging reconstructive procedure requiring reconstruction using autograft, allograft, or silastic (synthetic) implant.