Testicular Mixed Germ Cell Tumor (TMGCT) Management: Addressing Infection and Tumor Marker Dynamics.

We report the case of a 23-year-old male presenting with right testicular swelling, post-coital pain, and fever. Initial MRI and local examination suggested testicular carcinoma. Elevated serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) levels were observed. Biopsy confirmed a mixed germ cell tumor (MGCT). Concurrently, the patient was diagnosed with an infection and treated with antibiotics. Remarkably, following antibiotic therapy, fever resolved, and tumor marker levels significantly decreased. Subsequent orchidectomy confirmed the diagnosis of MGCT. This case underscores the importance of recognizing and treating concurrent infections, which may influence both clinical presentation and tumor marker levels in testicular germ cell tumors.

Assembly of SARS-CoV-2 nucleocapsid protein with nucleic acid.

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-)protein into ribonucleoprotein particles (RNPs), 38 ± 10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to ancestral and mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining nucleocapsid protein variants in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerize via a recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multivalent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N-protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.

Percutaneous Needle Decompression: A Novel Approach Toward Treating Compartment Syndrome of the Leg.

Percutaneous needle decompression (PND) can be a successful alternative to open fasciotomies for acute compartment syndrome (ACS). We present the case of a 45-year-old male patient who survived a road traffic accident and developed ACS following his open fracture of the tibia and fibula. He was treated by performing PND on all compartments of the affected leg using a 24 gauge needle thus avoiding the complications of a double incision fasciotomy.

Evaluation of warfarin management in primary health care centers in Qatar: A retrospective cross-sectional analysis of the national dataset.

BACKGROUND: Warfarin management is associated with severe complications, highlighting the critical need to evaluate the quality of its administration. OBJECTIVES: To evaluate the quality of warfarin management for patients managed in primary healthcare centers by measuring the percentage of Time in Therapeutic Range (TTR) and the proportion of extreme out-of-range international normalized ratio (INR) values. METHODS: This is a cross-sectional study. Data was extracted from a national dataset retrieved from the largest primary healthcare provider in Qatar. TTR was calculated using the traditional method. Inferential and descriptive analyses were performed as appropriate. RESULTS: Four hundred ninety-four patients met the inclusion criteria. The mean (SD) TTR was 45.3 % (17.5). This was significantly lower than the recommended cutoff value (P<0.001). Extreme out-of-range INR accounted for 24.7 % of total INR readings. CONCLUSIONS: The management of patients taking warfarin in Qatar is inadequate. More effective strategies are warranted to ensure safe and effective therapy.

Assembly reactions of SARS-CoV-2 nucleocapsid protein with nucleic acid.

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-) protein into ribonucleoprotein particles (RNPs), 38±10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining mutant proteins in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerize via a recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multi-valent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N-protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell Disorder, and Skin Changes) Syndrome as a Sequela of Castleman Disease: A Case Report.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a rare multisystemic paraneoplastic disorder caused by an underlying plasma cell dyscrasia. Its diagnosis is based on the presence of two mandatory criteria and at least one major and one minor criterion. We report a case of a 52-year-old female patient who presented with complaints of acrocyanosis, night sweats, scaly skin, and swelling on the left side of the neck. She was a known case of hypothyroidism, antiphospholipid syndrome, and cerebral venous thrombosis, and had other comorbidities as well. She also exhibited weakness and paresthesia of the limbs and muscle wasting in the hands. All necessary examinations and investigations were performed and the patient was eventually diagnosed with POEMS syndrome. She underwent chemotherapy along with immunotherapy initially, but as the disease relapsed, she was referred for high-dose therapy (HDT) and autologous stem cell transplantation.

Efficacy of Terbinafine and Itraconazole Combination Therapy Versus Terbinafine or Itraconazole Monotherapy in the Management of Fungal Diseases: A Systematic Review and Meta-Analysis.

Fungal infections constitute a common dermatological illness rampant in underdeveloped countries. Combination drug therapy is becoming increasingly well-established owing to drug resistance because of monotherapy. Different studies have been conducted previously to compare the medical regimens for the treatment of fungal infections. However, there is insufficient research on the difference in cure rates and recurrence rates with each regimen. To the best of our knowledge, this meta-analysis is the first to compare the effect of the most widely used oral antifungal medications and their combination usage. A meta-analysis of randomized controlled trials (RCTs) assesses the efficacy of terbinafine or itraconazole monotherapy versus combination therapy in fungal diseases. We queried PubMed and Cochrane Central from their inception to April 2022 for published studies, RCTs, and observational studies without any language restriction that compared itraconazole and terbinafine combination therapy with monotherapy in patients with fungal infections. The results from the studies were presented as risk ratios (RRs) with 95% confidence intervals (CIs) and were pooled using a random-effects model, and a p-value of ≤0.05 was considered significant for the analysis. Endpoints of interest included cure rates and recurrence rates. Cure rates were increased significantly for combination therapy compared to terbinafine monotherapy (RR=2.01 (1.37, 2.94); p=0.0003; I2=67%). On sensitivity analysis, a significant association was observed between combination therapy and itraconazole monotherapy in terms of cure rates (RR=1.91 (1.41, 2.57); p<0.0001; I2=0%) and recurrence rates (RR=0.08 (0.02, 0.44); p=0.003; I2=0%). The findings of this meta-analysis suggest that itraconazole and terbinafine combination therapy has a better cure rate when compared to terbinafine monotherapy.

Moebius Syndrome: An Updated Review of Literature.

Moebius Syndrome, is a rare, non-progressive congenital neuropathological syndrome characterized primarily by the underdevelopment of the facial (CN VII) and abducens nerve (CN VI). Other features of Moebius Syndrome include facial nerve paresis, ophthalmoplegias, orthodontic deficiencies (including crowded dentition, swollen and hyperplastic gingiva, dental calculus, etc.), musculoskeletal abnormalities, and impaired mental function. Due to the rarity of the disorder, very few case studies have been reported in the literature. This article summarizes the significant features of the disease according to commonalities in reported cases, along with several newly recognized features cited in recent literature. We have explored the different diagnostic criteria and the newly recognized imaging modalities that may be used. Understandably, the condition detrimentally affects a patient's quality of life; thus, treatment measures have also been outlined. This study aims to provide updated literature on Moebius Syndrome MBS and improve understanding of the condition.

Assembly of SARS-CoV-2 ribonucleosomes by truncated N∗ variant of the nucleocapsid protein.

The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compacts the RNA genome into viral ribonucleoprotein (vRNP) complexes within virions. Assembly of vRNPs is inhibited by phosphorylation of the N protein serine/arginine (SR) region. Several SARS-CoV-2 variants of concern carry N protein mutations that reduce phosphorylation and enhance the efficiency of viral packaging. Variants of the dominant B.1.1 viral lineage also encode a truncated N protein, termed N∗ or Δ(1-209), that mediates genome packaging despite lacking the N-terminal RNA-binding domain and SR region. Here, we use mass photometry and negative stain electron microscopy to show that purified Δ(1-209) and viral RNA assemble into vRNPs that are remarkably similar in size and shape to those formed with full-length N protein. We show that assembly of Δ(1-209) vRNPs requires the leucine-rich helix of the central disordered region and that this helix promotes N protein oligomerization. We also find that fusion of a phosphomimetic SR region to Δ(1-209) inhibits RNA binding and vRNP assembly. Our results provide new insights into the mechanisms by which RNA binding promotes N protein self-association and vRNP assembly, and how this process is modulated by phosphorylation.

Previous exposure to Spike-providing parental strains confers neutralizing immunity to XBB lineage and other SARS-CoV-2 recombinants in the context of vaccination.

The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as "Deltacron." We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.

SARS-CoV-2 variants evolve convergent strategies to remodel the host response.

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.

Life-threatening pontine hemorrhage secondary to HELLP syndrome.

HELLP syndrome is a severe form of pre-eclampsia that typically develops prior to delivery but can sometimes happen postpartum. The classic triad of HELLP syndrome comprises of hemolysis, elevated liver enzyme levels, and low platelet counts. This condition is known to have a higher incidence of fatal neurological complications, such as pontine hemorrhage, when compared to a typical pre-eclampsia.

Toward Predicting Nanoparticle Distribution in Heterogeneous Tumor Tissues.

Nanobio interaction studies have generated a significant amount of data. An important next step is to organize the data and design computational techniques to analyze the nanobio interactions. Here we developed a computational technique to correlate the nanoparticle spatial distribution within heterogeneous solid tumors. This approach led to greater than 88% predictive accuracy of nanoparticle location within a tumor tissue. This proof-of-concept study shows that tumor heterogeneity might be defined computationally by the patterns of biological structures within the tissue, enabling the identification of tumor patterns for nanoparticle accumulation.

Oral myiasis: A known case of scar epilepsy in a 45-year-old.

Key Clinical Message: Oral myiasis (OM) is brought on by parasitic larvae that consume both living and dead tissue. Our study aims to present the possible circumstances under which people suffer from this deteriorating condition in juxtaposition to scar epilepsy. Abstract: A uncommon disease known as oral myiasis (OM) is brought on by parasitic larvae that consume both living and dead tissue. OM cases in humans are scarce, although most of those reported come from developing nations or tropical regions. This case report describes a rare larvae infestation in the oral cavity of a 45-year-old woman who had previously undergone a ventriculoperitoneal (VP) shunt procedure, convulsions, and fever. The patient presented with episodic grand-mal seizures accompanied by fever for 2 days. She is a known case of scar epilepsy and underwent VP shunting due to hydrocephalus post-meningoencephalitis 16 years ago. The patient subsequently underwent symptomatic treatment and was later diagnosed with OM during her management. Histopathology of the biopsy following wound debridement revealed invasive fungal growth causing necrosis and erosion of the buccal mucosa and palate with no evidence of malignancy. The presentation of OM is an infrequent and exclusively rare entity. Our study aims to present the possible circumstances under which people suffer from this deteriorating condition in juxtaposition to scar epilepsy. This case report highlights the significance of prompt medicinal intervention and debridement coupled with preventative measures undertaken for a better prognosis and longevity.

Cell-derived nanovesicles from mesenchymal stem cells as extracellular vesicle-mimetics in wound healing.

Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers. Recently, extracellular vesicles (EVs), naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins, lipids, and nucleic acids, have drawn wide attention due to their ability to promote wound healing and tissue regeneration. However, current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes. To circumvent these challenges, bioinspired cell-derived nanovesicles (CDNs) that mimic EVs were obtained by shearing mesenchymal stem cells (MSCs) through membranes with different pore sizes. Physical characterisations and high-throughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs. Moreover, these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway, resulting in enhancement of cell proliferation, cell migration, secretion of growth factors and extracellular matrix proteins, which all promoted tissue regeneration. Of note, MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEG-fibrin scaffold and animal model, accelerating wound healing in vitro and in vivo. These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.

Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.

Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.

COVID-19Base v3: Update of the knowledgebase for drugs and biomedical entities linked to COVID-19.

COVID-19 has taken a huge toll on our lives over the last 3 years. Global initiatives put forward by all stakeholders are still in place to combat this pandemic and help us learn lessons for future ones. While the vaccine rollout was not able to curb the spread of the disease for all strains, the research community is still trying to develop effective therapeutics for COVID-19. Although Paxlovid and remdesivir have been approved by the FDA against COVID-19, they are not free of side effects. Therefore, the search for a therapeutic solution with high efficacy continues in the research community. To support this effort, in this latest version (v3) of COVID-19Base, we have summarized the biomedical entities linked to COVID-19 that have been highlighted in the scientific literature after the vaccine rollout. Eight different topic-specific dictionaries, i.e., gene, miRNA, lncRNA, PDB entries, disease, alternative medicines registered under clinical trials, drugs, and the side effects of drugs, were used to build this knowledgebase. We have introduced a BLSTM-based deep-learning model to predict the drug-disease associations that outperforms the existing model for the same purpose proposed in the earlier version of COVID-19Base. For the very first time, we have incorporated disease-gene, disease-miRNA, disease-lncRNA, and drug-PDB associations covering the largest number of biomedical entities related to COVID-19. We have provided examples of and insights into different biomedical entities covered in COVID-19Base to support the research community by incorporating all of these entities under a single platform to provide evidence-based support from the literature. COVID-19Base v3 can be accessed from: https://covidbase-v3.vercel.app/. The GitHub repository for the source code and data dictionaries is available to the community from: https://github.com/91Abdullah/covidbasev3.0.

Research Methodology and Mechanisms of Action of Current Orthopaedic Implant Coatings.

Orthopedic implants are crucial interventions that are gaining greater importance in modern medicine to restore function to commonly affected joints. Each implantation carries the risk of implant-associated infection and loosening of the implant due to improper integration with soft tissue. Coating strategies have been developed to aid the growth of bone into the implant (osteointegration) and prevent biofilm formation to avoid infection. In this review, primary articles highlighting recent developments and advancements in orthopedic implant coating will be presented. Additionally, the methodology of the articles will be critiqued based on this research criteria: establishment of function on a theoretical basis, validation of coating function, and potential next steps/improvements based on results. A theoretical basis based on understanding the mechanisms at play of these various coatings allows for systems to be developed to tackle the tasks of osteointegration, subversion of infection, and avoidance of cytotoxicity. The current state of research methodology in coating design focuses too heavily on either osteointegration or the prevention of infection, thus, future development in medical implant coating needs to investigate the creation of a coating that accomplishes both tasks. Additionally, next steps and improvements to systems need to be better highlighted to move forward when problems arise within a system. Research currently showcasing new coatings is performed primarily in vitro and in vivo. More clinical trials need to be performed to highlight long-term sustainability, the structural integrity, and the safety of the implant.

Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.

Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (30kb). Here, we designed a plasmid-based viral genome assembly and resc ue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.