Salvage Reconstruction of Composite Defects of the Anterior Mandible, Floor of Mouth, and Lip.

Anterior mandible defects result in loss of support for the tongue, floor of the mouth and lower lip, resulting in impairment of airway, feeding, and speech. We treated four patients with these "Andy Gump" deformities. Reconstruction was performed with two free flaps: a fibula osteocutaneous flap for the anterior mandible and floor of the mouth, and a soft tissue free flap for the lip, chin, and anterior neck. The lower lip was suspended cranially with fascia or tendon grafts ± mini-temporalis turndown flaps. All flaps survived completely. All patients were tube feed-dependent before surgery; they all resumed an oral diet. All tracheostomies were decannulated. Lip competence was restored as evidenced by cessation of drooling. Speech improved from unintelligible to intelligible with frequent repetitions. Objective assessment was performed with the functional intraoral Glasgow scale; the mean FIGS score improved from 3.25 (range 3-4) to 11 (range 9-13). We conclude that composite anterior mandible and tongue defects have large tissue requirements that require multiple free flaps. Reconstruction leads to significant improvement in function.

Optimising Laparoscopic Artificial Insemination in Lohi Sheep: Effects of Timing, Sperm Concentration and Body Condition on Fertility Outcome in Subtropical Climates.

The objective of this study was to determine the optimal timing, sperm concentration, and body condition score (BCS) for laparoscopic artificial insemination (LAI) in the subtropical Lohi sheep breed. In Experiment 1, Lohi ewes (n = 80) were synchronised through progestin-sponges (day 0-day 11), administering PGF2α (d-cloprostenol 75 µg/mL; i.m. @ 75 µg /ewe) on day 09 and eCG (i.m. @ 300 IU/ewe) on day 11. Ewes were divided equally into four groups (n = 20 each) and then LAI was performed at 48 (T48), 60 (T60), 72 (T72) and 96 (T96) hours post-sponge removal using 200 million sperm/insemination. In Experiment 2, ewes (n = 81) were synchronised as in Experiment I. Following synchronisation ewes were divided into four groups, each subjected to LAI employing varying sperm concentrations: 10 (S10; n = 21), 20 (S20; n = 20), 50 (S50; n = 20), or 100 (S100; n = 20) million per insemination. Inseminations were performed within a time window of 48-60 h post-sponge removal, based on the findings from Experiment 1. In both experiments ewes were categorised according to BCS, that is, medium 3 and high > 3. Results of Experiment 1 revealed a quadratic response that ewes inseminated at 60-h post-sponge removal exhibited significantly higher pregnancy and twinning rates (p = 0.02). The results of Experiment 2 revealed that sperm concentration had a quadratic effect, 50 million sperm per insemination resulted in maximal pregnancy rates (p = 0.01). Additionally, ewes with medium BCS (≤ 3) had higher pregnancy rates than high BCS (> 3) ewes. In conclusion, ewes with medium BCS (≤ 3) are ideal candidate for LAI and can be inseminated at 60 h with minimal sperm 50 × 106/dose post-sponge removal to achieve a maximum pregnancy rate.

Mechanism of probiotics in the intervention of colorectal cancer: a review.

The human microbiome interacts with the host mainly in the intestinal lumen, where putrefactive bacteria are suggested to promote colorectal cancer (CRC). In contrast, probiotics and their isolated components and secreted substances, display anti-tumor properties due to their ability to modulate gut microbiota composition, promote apoptosis, enhance immunity, resist oxidation and alter metabolism. Probiotics help to form a solid intestinal barrier against damaging agents via altering the gut microbiota and preventing harmful microbes from colonization. Probiotic strains that specifically target essential proteins involved in the process of apoptosis can overcome CRC resistance to apoptosis. They can increase the production of anti-inflammatory cytokines, essential in preventing carcinogenesis, and eliminate cancer cells by activating T cell-mediated immune responses. There is a clear indication that probiotics optimize the antioxidant system, decrease radical generation, and detect and degrade potential carcinogens. In this review, the pathogenic mechanisms of pathogens in CRC and the recent insights into the mechanism of probiotics in CRC prevention and therapy are discussed to provide a reference for the actual application of probiotics in CRC.

Anti-AMPA receptor encephalitis with myasthenia gravis: A sinister combination associated with a high risk for underlying malignancy.

A rare subtype of autoimmune encephalitis consists of antibodies targetting the alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor in the central nervous system. We describe the clinical presentation and autoimmune profile of the first case of alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis with concurrent anti-acetylcholine receptor antibodies in Pakistan. The patient was a 58-year-old male who presented with the characteristic symptoms of limbic encephalitis with memory loss, irritability, agitation, and confusion. Antibodies against the alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptor were detected in both serum and cerebrospinal fluid by indirect immunofluorescence. Computerised tomography of the chest showed an anterior mediastinal mass. The patient was treated with high dose Methylprednisolone and five sessions of plasma exchange. There was a short period of improvement; however, the patient now continues to exhibit irritability, aphasia, confusion, and memory loss. Video-assisted thoracoscopic surgery for mediastinal mass resection and histological testing was planned, however after review by the interventional radiologist the associated risks were deemed too high to proceed with the procedure and biopsy was not done.

When to feed after percutaneous endoscopic gastrostomy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Initiation of feeding after percutaneous endoscopic gastrostomy (PEG) placement has been debated. Randomized controlled trials (RCTs) have been performed on early feeding compared with delayed feeding after PEG placement with varying results. Therefore, a meta-analysis was conducted examining early vs delayed feeding after placement of a PEG. METHODS: A comprehensive search of databases was conducted in January 2024. Peer-reviewed published RCTs comparing early feeding (≤4 h) with delayed feeding (>4 h) were identified and included in the meta-analysis. Meta-analysis was completed using pooled estimates of overall complications, individual complications, mortality ≤72 h, and number of day 1 significant gastric residual volumes. RESULTS: Six RCTs (n = 467) were included in the analysis. Comparison of early feeding with delayed feeding after PEG showed no statistically significant differences for overall complications (P = 0.18), mortality ≤72 h (P = 0.3), and number of day 1 significant gastric residual volumes (P = 0.05). No differences were also noted for individual complications, including vomiting, wound infection, bleeding, or diarrhea. CONCLUSION: Feeding ≤4 h after PEG have no differences in minor and major complications compared with that of delayed feeding. Early feeding ≤4 h is safe and should be recommended in future guidelines.

Advancing Perioperative Neurocognitive Health: A Critical Review of Predictive Tools, Diagnostic Methods, and Interventional Strategies.

Perioperative neurocognitive disorders (PNDs) affect a large percentage of people who undergo surgeries that need general anesthesia. There is an increased risk of death and a major disruption to postoperative self-care as a result of this. This study compiles all the relevant materials that the authors have found to investigate postnatal depression and its causes, as well as the methods used to determine the probability and severity of PNDs and how to reduce their risk before surgery. Postnatal depression can have many causes, and this text explores some of them. These include a history of alcohol or opiate use, immunological dysregulation, advanced age, educational background, infections, neurocognitive impairment, and pre-existing chronic inflammatory disorders. It also delves into various methods used to gauge the likelihood and severity of postpartum depression. The following assessment tools were covered: the Clock Drawing Test, Domain-Specific Tests, the Mini-Mental State Examination, and the Montreal Cognitive Assessment. In addition to biochemical markers, neuroimaging techniques play an important role in diagnosis. The Frailty Fried assessment, which measures inertia, sluggishness, lack of physical activity, fatigue, and unintentional weight loss, is a key prognostic sign that is highlighted. There is strong evidence that the index, which is derived from these five characteristics, may accurately predict the likelihood of PNDs. Risk mitigation strategies are also covered in this research. Preoperative brain plasticity-based therapies, such as physical exercise and intensive cognitive training, can significantly reduce the incidence and severity of postoperative neurocognitive disorders. A peripheral nerve block, monitoring cerebral oxygen saturation, dexmedetomidine, and a reduction in anesthesia depth are all ways to improve anesthetic procedures. Methods that lower blood pressure should be avoided, the body temperature should be kept down during surgery, or the time without liquids should be lengthened; all of these raise the risk of postoperative nausea and vomiting and make it worse. Potential approaches include a Mediterranean diet, physical activity, cognitive stimulation, smoking cessation, alcohol reduction, avoidance of anticholinergic medications, and non-steroidal anti-inflammatory drug stewardship, although there is no definitive evidence for successful postoperative neurocognitive rehabilitation procedures. More standardized diagnostic criteria, evaluation methods, and PND classification are urgently needed, according to this study. Different cases of PNDs are characterized by different combinations of tests, cutoff values, and methods because there is a broad variety of diagnostic tests used to make the diagnosis. Until now, PNDs and pre-existing neurocognitive disorders have been diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). With an aging population comes an increase in the occurrence and prevalence of PNDs, which calls for a specific way to classify and describe the condition.

Factors influencing pregnancy rate and loss after laparoscopic artificial insemination with frozen-thawed semen in Lohi sheep under sub-tropical conditions.

This study evaluates factors influencing pregnancy rates per artificial insemination (P/AI) and pregnancy loss in Lohi ewes undergoing laparoscopic AI with frozen-thawed semen under sub-tropical conditions. Data from three experiments comprising ewes (n = 358) of mixed parity (nulliparous; NP and parous; P), various body condition score (BCS) and assigned to long-term (LTP, 11 days) and short-term (STP, 5 days) oestrus synchronization regimen across high breeding season (HBS) and low breeding season (LBS) were analysed. Laparoscopic insemination was conducted 54 h post-sponge removal. Pregnancy diagnosis and loss were evaluated on days 35 and 90 post-insemination via ultrasonography. Results showed parity significantly influenced P/AI, with nulliparous ewes achieving higher pregnancy ratios than parous ewes (p = .001). BCS significantly influenced P/AI (p < .05), with a quadratic relationship observed between BCS and season (BCS*BCS*Season; p = .07). Progestin treatment did not significantly influence the ratio of pregnant ewes (p = .07). Pregnancy losses were significantly higher during LBS than HBS (p < .05), irrespective of progestin treatment. In conclusion, parity and BCS significantly influenced P/AI, with BCS demonstrating a quadratic association with season. Ewes bred during LBS experienced higher pregnancy losses than HBS, irrespective of progestin treatment.

Exploring dermoscopic structures for melanoma lesions' classification.

Background: Melanoma is one of the deadliest skin cancers that originate from melanocytes due to sun exposure, causing mutations. Early detection boosts the cure rate to 90%, but misclassification drops survival to 15-20%. Clinical variations challenge dermatologists in distinguishing benign nevi and melanomas. Current diagnostic methods, including visual analysis and dermoscopy, have limitations, emphasizing the need for Artificial Intelligence understanding in dermatology. Objectives: In this paper, we aim to explore dermoscopic structures for the classification of melanoma lesions. The training of AI models faces a challenge known as brittleness, where small changes in input images impact the classification. A study explored AI vulnerability in discerning melanoma from benign lesions using features of size, color, and shape. Tests with artificial and natural variations revealed a notable decline in accuracy, emphasizing the necessity for additional information, such as dermoscopic structures. Methodology: The study utilizes datasets with clinically marked dermoscopic images examined by expert clinicians. Transformers and CNN-based models are employed to classify these images based on dermoscopic structures. Classification results are validated using feature visualization. To assess model susceptibility to image variations, classifiers are evaluated on test sets with original, duplicated, and digitally modified images. Additionally, testing is done on ISIC 2016 images. The study focuses on three dermoscopic structures crucial for melanoma detection: Blue-white veil, dots/globules, and streaks. Results: In evaluating model performance, adding convolutions to Vision Transformers proves highly effective for achieving up to 98% accuracy. CNN architectures like VGG-16 and DenseNet-121 reach 50-60% accuracy, performing best with features other than dermoscopic structures. Vision Transformers without convolutions exhibit reduced accuracy on diverse test sets, revealing their brittleness. OpenAI Clip, a pre-trained model, consistently performs well across various test sets. To address brittleness, a mitigation method involving extensive data augmentation during training and 23 transformed duplicates during test time, sustains accuracy. Conclusions: This paper proposes a melanoma classification scheme utilizing three dermoscopic structures across Ph2 and Derm7pt datasets. The study addresses AI susceptibility to image variations. Despite a small dataset, future work suggests collecting more annotated datasets and automatic computation of dermoscopic structural features.

Impact of frailty on endoscopic retrograde cholangiopancreatography outcomes in nonagenarians: A United States national experience.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an essential therapeutic tool for biliary and pancreatic diseases. Frail and elderly patients, especially those aged ≥ 90 years are generally considered a higher-risk population for ERCP-related complications. AIM: To investigate outcomes of ERCP in the Non-agenarian population (≥ 90 years) concerning Frailty. METHODS: This is a cohort study using the 2018-2020 National Readmission Database. Patients aged ≥ 90 were identified who underwent ERCP, using the international classification of diseases-10 code with clinical modification. Johns Hopkins's adjusted clinical groups frailty indicator was used to classify patients as frail and non-frail. The primary outcome was mortality, and the secondary outcomes were morbidity and the 30 d readmission rate related to ERCP. We used univariate and multivariate regression models for analysis. RESULTS: A total of 9448 patients were admitted for any indications of ERCP. Frail and non-frail patients were 3445 (36.46%) and 6003 (63.53%) respectively. Indications for ERCP were Choledocholithiasis (74.84%), Biliary pancreatitis (9.19%), Pancreatico-biliary cancer (7.6%), Biliary stricture (4.84%), and Cholangitis (1.51%). Mortality rates were higher in frail group [adjusted odds ratio (aOR) = 1.68, P = 0.02]. The Intra-procedural complications were insignificant between the two groups which included bleeding (aOR = 0.72, P = 0.67), accidental punctures/lacerations (aOR = 0.77, P = 0.5), and mechanical ventilation rates (aOR = 1.19, P = 0.6). Post-ERCP complication rate was similar for bleeding (aOR = 0.72, P = 0.41) and post-ERCP pancreatitis (aOR = 1.4, P = 0.44). Frail patients had a longer length of stay (6.7 d vs 5.5 d) and higher mean total charges of hospitalization ($78807 vs $71392) compared to controls (P < 0.001). The 30 d all-cause readmission rates between frail and non-frail patients were similar (P = 0.96). CONCLUSION: There was a significantly higher mortality risk and healthcare burden amongst nonagenarian frail patients undergoing ERCP compared to non-frail. Larger studies are warranted to investigate and mitigate modifiable risk factors.

Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.

Cancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of -242 kcal/mol for wild-type, while the mutant complexes had scores ranging from -217 to -220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was -64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were -45.90 kcal/mol, -53.52 kcal/mol, -55.67 kcal/mol, and -61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.

Cassia Angustifolia Primed ASCs Accelerate Burn Wound Healing by Modulation of Inflammatory Response.

BACKGROUND: Thermal traumas impose a huge burden on healthcare systems. This merits the need for advanced but cost-effective remedies with clinical prospects. In this context, we prepared a regenerative 3D-construct comprising of Cassia angustifolia extract (SM) primed adipose-derived stem cells (ASCs) laden amniotic membrane for faster burn wound repair. METHODS: ASCs were preconditioned with SM (30 µg/ml for 24 h), and subsequently exposed to in-vitro thermal injury (51 °C,10 min). In-vivo thermal injury was induced by placing pre-heated copper-disc (2 cm diameter) on dorsum of the Wistar rats. ASCs (2.0 × 105) pre-treated with SM (SM-ASCs), cultured on stromal side of amniotic membrane (AM) were transplanted in rat heat-injury model. Non-transplanted heat-injured rats and non-heat-injured rats were kept as controls. RESULTS: The significantly upregulated expression of IGF1, SDF1A, TGFß1, VEGF, GSS, GSR, IL4, BCL2 genes and downregulation of BAX, IL6, TNFα, and NFkB1 in SM-ASCs in in-vitro and in-vivo settings confirmed its potential in promoting cell-proliferation, migration, angiogenesis, antioxidant, cell-survival, anti-inflammatory, and wound healing activity. Moreover, SM-ASCs induced early wound closure, better architecture, normal epidermal thickness, orderly-arranged collagen fibers, and well-developed skin appendages in healed rat-skin transplanted with AM+SM-ASCs, additionally confirmed by increased expression of structural genes (Krt1, Krt8, Krt19, Desmin, Vimentin, α-Sma) in comparison to untreated-ASCs laden-AM transplanted in heat injured rats. CONCLUSION: SM priming effectively enabled ASCs to counter thermal injury by significantly enhancing cell survival and reducing inflammation upon transplantation. This study provides bases for development of effective combinational therapies (natural scaffold, medicine, and stem cells) with clinical prospects for treating burn wounds.

Heart rate as an indicator of stress during the critical swimming speed test of farmed Atlantic salmon (Salmo salar L.).

A swim tunnel is to fish as a treadmill is to humans, and is a device used for indirect measuring of the metabolic rate. This study aims to explore the fish stress (if any) during the critical swimming test routines (fish handling, confinement, and swimming) using heart rate (fH , heartbeat per minute) bio-loggers in farmed Atlantic salmon (Salmo salar L.). In addition, the recovery dynamics of exercised fish using fH were explored for 48 h post swim tests. Continuous fH data were acquired following the surgical implantation and throughout the trials, such as during fish handling, swim tests (critical swimming speed, Ucrit ), and 48 h post swim tests. After 3 weeks of surgical recovery, fH stabilized at 46.20 ± 1.26 beats min-1 , equalizing a ~38% reduction in fH recorded post-surgical tachycardia (74.13 ± 1.44 beats min-1 ). Interestingly, fH was elevated by ~200% compared to baseline levels not only due to the Ucrit (92.04 ± 0.23 beats min-1 ) but also due to fish handling and confinement in the swim tunnel, which was 66% above the baseline levels (77.48 ± 0.34 beats min-1 ), suggesting fish stress. Moreover, significantly higher plasma cortisol levels (199.56 ± 77.17 ng mL-1 ) corresponding to a ~300% increase compared to baseline levels (47.92 ± 27.70 ng mL-1 ) were identified after Ucrit , predicting post-swim test stress (physiological exhaustion). These findings reinforce the importance of fish acclimation in the swim tunnel prior to the swimming tests. However, fH dropped over the course of the 48-h post-swim test, but remained comparatively higher than the basal levels, suggesting fish should be given at least 48 h to recover from handling stress for better fish welfare. This study further explored the influence of fish tagging on Ucrit , which resulted in reduced swimming capabilities of tagged fish (1.95 ± 0.37 body lengths s-1 ) compared to untagged fish (2.54 ± 0.42 body length s-1 ), although this was not significant (p = 0.06), and therefore future tagging studies are warranted.

Computational investigation of Moringa oleifera phytochemicals targeting EGFR: molecular docking, molecular dynamics simulation and density functional theory studies.

Epidermal growth factor receptor (EGFR) is a prominent target for anticancer therapy due to its role in activating several cell signaling cascades. Clinically approved EGFR inhibitors are reported to show treatment resistance and toxicity, this study, therefore, investigates Moringa oleifera phytochemicals to find potent and safe anti-EGFR compounds. For that, phytochemicals were screened based on drug-likeness and molecular docking analysis followed by molecular dynamics simulation, density functional theory analysis and ADMET analysis to identify the effective inhibitors of EGFR tyrosine kinase (EGFR-TK) domain. Known EGFR-TK inhibitors (1-4 generations) were used as control. Among 146 phytochemicals, 136 compounds showed drug-likeness, of which Delta 7-Avenasterol was the most potential EGFR-TK inhibitor with a binding energy of -9.2 kcal/mol followed by 24-Methylenecholesterol (-9.1 kcal/mol), Campesterol (-9.0 kcal/mol) and Ellagic acid (-9.0 kcal/mol). In comparison, the highest binding affinity from control drugs was displayed by Rociletinib (-9.0 kcal/mol). The molecular dynamics simulation (100 ns) exhibited the structural stability of native EGFR-TK and protein-inhibitor complexes. Further, MM/PBSA computed the binding free energies of protein complex with Delta 7-Avenasterol, 24-Methylenecholesterol, Campesterol and Ellagic acid as -154.559 ± 18.591 kJ/mol, -139.176 ± 19.236 kJ/mol, -136.212 ± 17.598 kJ/mol and -139.513 ± 23.832 kJ/mol, respectively. Non-polar interactions were the major contributors to these energies. The density functional theory analysis also established the stability of these inhibitor compounds. ADMET analysis depicted acceptable outcomes for all top phytochemicals without displaying any toxicity. In conclusion, this report has identified promising EGFR-TK inhibitors to treat several cancers that can be further investigated through laboratory and clinical tests.

Gastric Glomus Tumors: The Roles of Endoscopic Ultrasound and Shared Decision-Making.

Gastric glomus tumors (GGTs) are mesenchymal neoplasms with indolent behavior that originate from the subepithelial layers of the stomach and represent up to 1% of all gastric tumors. GGT is detected incidentally during esophagogastroduodenoscopy (EGD) in a proportion of patients. Endoscopic ultrasound (EUS) evaluation of GGT is essential to establish the diagnosis and to differentiate it from gastrointestinal stromal tumors or gastric neuroendocrine tumors. An 80-year-old man who presented for abdominal discomfort was incidentally found to have a gastric antral nodule on EGD. Endoscopic biopsy demonstrated moderately erythematous gastric antral mucosa and a 1.5 cm subepithelial lesion along the greater curvature. An EUS revealed a subepithelial 1.6 cm × 1.3 cm isoechoic, homogenous lesion with small calcifications. Immunohistochemical staining of the fine needle biopsy specimen of the nodule was positive for neoplastic cells, smooth muscle actin, vimentin, patchy muscle-specific actin, and synaptophysin. There were no atypical cytologic features. These findings were consistent with GGT. The patient was not deemed to be a candidate for surgical resection due to advanced age and resolution of his symptoms. A shared decision was made to pursue regular surveillance. EUS is essential for evaluation of GGT. Currently, there are no guideline recommendations for surveillance of GGT detected on routine EGD in asymptomatic individuals. A definitive surgical treatment with partial gastrectomy was favored in previously published literature. For asymptomatic patients with GGT or those with resolution of symptoms, careful surveillance with serial abdominal imaging and EUS may be a reasonable option, especially in older patients with poor surgical candidacy.

Overlapping Hepatotoxicity and Colitis Associated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are widely used for the management of many solid-organ and hematologic cancers. These agents work by inhibition of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and PD ligand 1 (PD-L1). Hyperactivation of immune system results in ICI-associated adverse events. Simultaneous hepatotoxicity and colitis associated with ICIs is rare and potentially overlooked, as clinical symptoms are often nonspecific. A 73-year-old man with metastatic squamous cell carcinoma presented six weeks after starting pembrolizumab with abdominal discomfort and diarrhea. Pembrolizumab therapy was held, and supportive therapy with antidiarrheals provided partial relief. After initial workup, ICI-associated hepatitis (ICIH) and ICI-related colitis (ICIC) were diagnosed. Colitis resolution required corticosteroids. This case illustrates the importance of high index of clinical suspensions for gastrointestinal and hepatic adverse events associated with ICIs, which may be overlooked and result in severe complications. While isolated ICIH and ICIC are well known adverse events, overlapping ICIH and ICIC is rare. Prompt recognition, cessation of the inciting agent, and initiation of early supportive therapy are essential. Treatment may require corticosteroids or mycophenolate mofetil.

In-silico prediction of TGF-ß1 non-synonymous variants and their impact on binding affinity to Fresolimumab.

TGF-ß1 is a potent immunoregulatory cytokine that plays diverse roles in development, bone healing, fibrosis, and cancer. However, characterizing TGF-ß1 gene variants is challenging because the structural and functional consequences of these variants are still undetermined. In this study, we aimed to perform an in-silico analysis of TGF-ß1 non-synonymous variants and their pathogenic effects on the TGF-ß1 protein. A total of 10,252 TGF-ß1 SNPs were collected from the NCBI dbSNP database and in-silico tools (SIFT, PROVEAN, Mutation Taster, ClinVar, PolyPhen-2, CScape, MutPred, and ConSurf) were used. The in-silico predicted potential variants were further investigated for their binding to the TGF-ß1 targeting drug "Fresolimumab". Molecular docking was performed using HADDOCK and confirmed by PRODIGY and PDBsum. The in-silico analysis predicted four potential TGF-ß1 nsSNPs: E47G in the LAP domain of the propeptide and I22T, L28F, and E35D in the mature TGF-ß1 peptide. HADDOCK and molecular dynamics simulations revealed that the I22T and E35D variants have higher binding affinity for Fresolimumab as compared to the wild type and L28F variants. Molecular dynamics simulations (100 ns) and principal component analysis showed that TGF-ß1 variants influenced the protein structure and caused variations in the internal dynamics of protein complexes with the antibody. Among them, the E35D variant significantly destabilized the TGF-ß1 protein structure, resulting in rearrangement in the binding site and affecting the interactions with the Fresolimumab. This study identified four variants that can affect the TGF-ß1 protein structure and result in functional consequences such as impaired response to Fresolimumab.Communicated by Ramaswamy H. Sarma.

Synergistic effect of extracellular adenosine triphosphate and quercetin on post-thaw quality and fertilization potential of Lohi ram sperm.

This study determined the individual and combined effects of extracellular adenosine triphosphate (ATP) and quercetin (QUE) on the quality of post-thawed sperm and the fertilization potential of Lohi rams. In experiment 1, semen samples from four Lohi rams were pooled and extended with different concentrations of ATP or QUE (control; no ATP or QUE, 1 or 2 mM ATP and 10 or 20 µM QUE). In experiment 2, pooled semen samples were extended with various combinations of ATP and QUE (control; no ATP and QUE, 1 mM ATP + 10 µM QUE, 1 mM ATP + 20 µM QUE, 2 mM ATP + 10 µM QUE and 2 mM ATP + 20 µM QUE). All samples in both experiments were cryopreserved and analyzed for post-thawed sperm quality. In experiment 3, the best combination of ATP and QUE from experiment 2 was to extend semen, which was then used for laparoscopic insemination in estrus-synchronized ewes (n = 83). The results of experiment 1 showed that 1 mM ATP and 20 µM QUE treatments resulted in higher total motility, progressive motility, viability, plasma membrane intactness (PMI), and motion kinetics (VCL, VSL, VAP, LIN, and STR) compared to other treatments (p < 0.05). In experiment 2, the 1 mM ATP +10 µM QUE-treated group exhibited significantly higher total and progressive motility, PMI, and motion kinetics (VSL, VCL, VAP, STR, and BCF) compared to the control group (p < 0.05). In experiment 3, the fertilizing potential of sperms treated with 1 mM ATP +10 µM QUE was greater than that of untreated controls (58.1% vs. 27.5%, respectively, p-value = 0.012). In conclusion, the quality of post-thawed ram semen is enhanced when the extender is supplemented with extracellular 1 mM ATP and 20 µM QUE, whether used separately or in combination with 1 mM ATP and 10 µM QUE. Furthermore, the inclusion of 1 mM ATP and 10 µM QUE together in the extender significantly improves in vivo fertility in Lohi ram.

EUS-guided versus percutaneous liver biopsy: A prospective randomized clinical trial.

Background and Objectives: Prospective studies comparing EUS-guided liver biopsy (EUS-LB) to percutaneous LB (PC-LB) are scarce. We compared the efficacy and safety of EUS-LB with those of PC-LB in a prospective randomized clinical trial. Methods: Between 2020 and 2021, patients were enrolled and randomized (1:1 ratio). The primary outcome was defined as the proportion of patients with ≥11 complete portal tracts (CPTs). The sample size (n = 80) was calculated based on the assumption that 60% of those in the EUS-LB and 90% of those in the PC-LB group will have LB with ≥11 CPTs. The secondary outcomes included proportion of patients in whom a diagnosis was established, number of CPTs, pain severity (Numeric Rating Scale-Pain Intensity), duration of hospital stay, and adverse events. Results: Eighty patients were enrolled (median age, 53 years); 67.5% were female. Sixty percent of those in the EUS-LB and 75.0% of those in the PC-LB group met the primary outcome (P = 0.232). The median number of CPTs was higher in the PC-LB (17 vs 13; P = 0.031). The proportion of patients in whom a diagnosis was established was similar between the groups (92.5% [EUS-LB] vs 95.0% [PC-LB]; P = 1.0). Patients in the EUS-LB group had less pain severity (median Numeric Rating Scale-Pain Intensity, 2.0 vs 3.0; P = 0.003) and shorter hospital stay (2.0 vs 4.0 hours; P < 0.0001) compared with the PC-LB group. No patient experienced a serious adverse event. Conclusions: EUS-guided liver biopsy was safe, effective, better tolerated, and associated with a shorter hospital stay.

Progressive Multifocal Encephalopathy Holmes Tremor Successfully Treated with Bilateral Deep Brain Stimulation.

Background: We report a patient with bilateral HT treated with DBS. Case report: A 58-year-old man diagnosed with HIV/AIDS and progressive multifocal leukoencephalopathy (PML) presented with 20 years of bilateral arm tremor refractory to therapy. DBS was implanted on the left ventral intermediate nucleus and posterior subthalamic area (VIM/PSA). One year later, a right VIM/PSA DBS was implanted. At twelve months, there were no significant side-effects. With his DBS turned off and on, the Fahn-Tolosa-Marin scale was rated 82 and 58, respectively. Discussion: To our knowledge, this is the first report of bilateral DBS VIM/PSA treating HT with no significant side effects. Highlights: We report a successful treatment using deep brain stimulation of bilateral Holmes tremor that was caused by progressive multifocal encephalopathy. The patient achieved 30% improvement in tremor control with a meaningful improvement in his activities of daily living.