Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus.

Rift Valley fever is a zoonotic viral disease transmitted by mosquitoes, impacting both humans and livestock. Currently, there are no approved vaccines or antiviral treatments for humans. This study aimed to evaluate the in vitro efficacy of chemical compounds targeting the Gc fusion mechanism. These compounds were identified through virtual screening of millions of commercially available small molecules using a structure-based artificial intelligence bioactivity predictor. In our experiments, a pretreatment with small molecule compounds revealed that 3 out of 94 selected compounds effectively inhibited the replication of the Rift Valley fever virus MP-12 strain in Vero cells. As anticipated, these compounds did not impede viral RNA replication when administered three hours after infection. However, significant inhibition of viral RNA replication occurred upon viral entry when cells were pretreated with these small molecules. Furthermore, these compounds exhibited significant inhibition against Arumowot virus, another phlebovirus, while showing no antiviral effects on tick-borne bandaviruses. Our study validates AI-based virtual high throughput screening as a rational approach for identifying effective antiviral candidates for Rift Valley fever virus and other bunyaviruses.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Graph Signal Processing, Graph Neural Network and Graph Learning on Biological Data: A Systematic Review.

Graph networks can model data observed across different levels of biological systems that span from population graphs (with patients as network nodes) to molecular graphs that involve omics data. Graph-based approaches have shed light on decoding biological processes modulated by complex interactions. This paper systematically reviews graph-based analysis methods of Graph Signal Processing (GSP), Graph Neural Networks (GNNs) and graph topology inference, and their applications to biological data. This work focuses on the algorithms of graph-based approaches and the constructions of graph-based frameworks that are adapted to a broad range of biological data. We cover the Graph Fourier Transform and the graph filter developed in GSP, which provides tools to investigate biological signals in the graph domain that can potentially benefit from the underlying graph structures. We also review the node, graph, and interaction oriented applications of GNNs with inductive and transductive learning manners for various biological targets. As a key component of graph analysis, we provide a review of graph topology inference methods that incorporate assumptions for specific biological objectives. Finally, we discuss the biological application of graph analysis methods within this exhaustive literature collection, potentially providing insights for future research in biological sciences.

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network.

Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

Scheimpflug Corneal Densitometry Values and Severity of Guttae in Relation to Visual Acuity in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this study was to investigate the association between corneal densitometry (CD) values from Scheimpflug tomography imaging, severity of guttae, and visual acuity in eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: This was a retrospective, cross-sectional study. Patients with FECD were examined at the Bascom Palmer Eye Institute from January 2015 to September 2019. We extracted CD values at central annuli of 0-2, 2-6, 6-10 and 10-12 mm from Scheimpflug tomography images. We investigated the association of corrected distance visual acuity (CDVA) with CD values, severity of guttae, central corneal thickness (CCT), cataract grade, refractive error, corneal edema grade, age, and gender using multivariate generalized estimating equation regression models. RESULTS: One hundred ninety-two eyes from 110 patients were included in this study. Increase in central CD values at the 0 to 2 mm zone (P < 0.001), severity of guttae (P = 0.046), age (P < 0.001), cataract grade (P < 0.001), corneal edema grade (P < 0.001), and type of refractive error (P = 0.008) were significantly associated with decreased CDVA. Central corneal thickness, sex, and the peripheral CD values (2-6, 6-10, and 10-12 mm) were not significantly associated with CDVA (P > 0.05) in the final multivariate regression model. CONCLUSIONS: Our study demonstrates that central CD values at 0 to 2 mm and severity of guttae are each associated with decreased CDVA in FECD. These findings carry implications for patients with FECD considering surgical intervention for phacoemulsification alone, Descemet stripping only, or endothelial cell transplantation and provide a multifactorial perspective on vision loss in FECD.

Considerations for Corneal Surgery With Patients in the 10th Decade of Life.

PURPOSE: The purpose of this study was to report the indications, ocular and systemic comorbidities, and surgical outcomes of corneal transplantation in patients older than 90 years. METHODS: A retrospective review was conducted to identify individuals 90 years and older who underwent corneal transplantation surgery at the Bascom Palmer Eye Institute between January 2013 and October 2020. Outcomes included best-corrected visual acuity and graft survival over time. Paired t tests were used to compare visual acuity preoperatively versus postoperatively. Graft survival was evaluated with Kaplan-Meier curves. RESULTS: Fifty-eight eyes of 52 consecutive individuals were included. The mean age of individuals was 92 ± 2 years; 26.9% were male; and 48.1% self-identified as non-Hispanic White and 38.5% as Hispanic. Postoperative follow-up was 14.7 ± 12.1 months. Of the 58 eyes, 44.8% (26/58) underwent penetrating keratoplasty, 46.6% (27/58) Descemet stripping automated endothelial keratoplasty, and 6.9% (4/58) keratoprosthesis. All surgeries were performed under monitored local anesthesia, without major complications. Surgical indications included pseudophakic bullous keratopathy (36.2%), glaucoma-associated corneal decompensation (27.6%), Fuchs endothelial dystrophy (25.9%), and perforated corneal ulceration (19.0%). The best-corrected visual acuity improved by 0.32 (95% confidence interval 0.14-0.50; P < 0.01) as early as 1 month postoperatively, and vision gains were sustained for at least 12 months. Graft survival probability at 12 months was 88%. CONCLUSIONS: Corneal transplantation is a safe and successful procedure in restoring the visual acuity for patients older than 90 years after careful preoperative evaluation. Further research is needed to evaluate the impact of corneal transplantation on quality of life in patients in the 10th decade of life.

Topical Ocular Povidone-Iodine as an Adjunctive Preventative Practice in the Era of COVID-19.

ABSTRACT: Ophthalmologists and patients have an inherent increased risk for transmission of SARS-CoV-2. The human ocular surface expresses receptors and enzymes facilitating transmission of SARS-CoV-2. Personal protective equipment alone provides incomplete protection. Adjunctive topical ocular, nasal, and oral antisepsis with povidone iodine bolsters personal protective equipment in prevention of provider-patient transmission of SARS-CoV-2 in ophthalmology.

Crystal Structure and Mechanistic Molecular Modeling Studies of Mycobacterium tuberculosis Diterpene Cyclase Rv3377c.

Terpenes make up the largest class of natural products, with extensive chemical and structural diversity. Diterpenes, mostly isolated from plants and rarely prokaryotes, exhibit a variety of important biological activities and valuable applications, including providing antitumor and antibiotic pharmaceuticals. These natural products are constructed by terpene synthases, a class of enzymes that catalyze one of the most complex chemical reactions in biology: converting simple acyclic oligo-isoprenyl diphosphate substrates to complex polycyclic products via carbocation intermediates. Here we obtained the second ever crystal structure of a class II diterpene synthase from bacteria, tuberculosinol pyrophosphate synthase (i.e., Halimadienyl diphosphate synthase, MtHPS, or Rv3377c) from Mycobacterium tuberculosis (Mtb). This enzyme transforms (E,E,E)-geranylgeranyl diphosphate into tuberculosinol pyrophosphate (Halimadienyl diphosphate). Rv3377c is part of the Mtb diterpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacterium species, but not in closely related avirulent species, and was proposed to be involved in phagolysosome maturation arrest. To gain further insight into the reaction pathway and the mechanistically relevant enzyme substrate binding orientation, electronic structure calculation and docking studies of reaction intermediates were carried out. Results reveal a plausible binding mode of the substrate that can provide the information to guide future drug design and anti-infective therapies of this biosynthetic pathway.

Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial.

OBJECTIVES: This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF). BACKGROUND: Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization. METHODS: In a pre-specified subgroup analysis, we examined changes in N-terminal pro-B-type natriuretic peptide, clinical outcomes, and safety according to race. RESULTS: The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro-B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44). CONCLUSIONS: Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

Multi-tiered screening and diagnosis strategy for COVID-19: a model for sustainable testing capacity in response to pandemic.

Coronavirus disease 2019 (COVID-19), caused by novel enveloped single stranded RNA coronavirus (SARS-CoV-2), is responsible for an ongoing global pandemic. While other countries deployed widespread testing as an early mitigation strategy, the U.S. experienced delays in development and deployment of organism identification assays. As such, there is uncertainty surrounding disease burden and community spread, severely hampering containment efforts. COVID-19 illuminates the need for a tiered diagnostic approach to rapidly identify clinically significant infections and reduce disease spread. Without the ability to efficiently screen patients, hospitals are overwhelmed, potentially delaying treatment for other emergencies. A multi-tiered, diagnostic strategy incorporating a rapid host immune response assay as a screening test, molecular confirmatory testing and rapid IgM/IgG testing to assess benefit from quarantine/further testing and provide information on population exposure/herd immunity would efficiently evaluate potential COVID-19 patients. Triaging patients within minutes with a fingerstick rather than hours/days after an invasive swab is critical to pandemic response as reliance on the existing strategy is limited by assay accuracy, time to results, and testing capacity. Early screening and triage is achievable from the outset of a pandemic with point-of-care host immune response testing which will improve response time to clinical and public health actions.Key messagesDelayed testing deployment has led to uncertainty surrounding overall disease burden and community spread, severely hampering public health containment and healthcare system preparation efforts.A multi-tiered testing strategy incorporating rapid, host immune point-of-care tests can be used now and for future pandemic planning by effectively identifying patients at risk of disease thereby facilitating quarantine earlier in the progression of the outbreak during the weeks and months it can take for pathogen specific confirmatory tests to be developed, validated and manufactured in sufficient quantities.The ability to triage patients at the point of care and support the guidance of medical and therapeutic decisions, for viral isolation or confirmatory testing or for appropriate treatment of COVID-19 and/or bacterial infections, is a critical component to our national pandemic response and there is an urgent need to implement the proposed strategy to combat the current outbreak.

COVID-19 and ophthalmology: an underappreciated occupational hazard.

The proximity required of a thorough biomicroscopic slit-lamp examination may put ophthalmologists at increased risk for respiratory-borne infection with SARS-CoV-2. Conjunctivitis has been described in a few patients with COVID-19 and other coronavirus syndromes. Although SARS-CoV-2 has been detected in the conjunctival secretions or tears of patients with COVID-19 and conjunctivitis, transmission of infection through respiratory droplets to ophthalmologists without eye protection or masks may be the bigger concern.

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.

Comparison of phacoemulsification parameters between manual and femtosecond laser-assisted cataract surgery.

OBJECTIVE: To compare the nucleus removal time (NRT) and cumulative dissipated energy (CDE) outcomes of traditional phacoemulsification and femtosecond laser-assisted cataract surgery (FLACS) performed by cornea attendings and fellows. DESIGN: Prospective nonrandomized comparative study. PARTICIPANTS: A total of 410 eyes of 410 patients. METHODS: Nucleus removal time and CDE were recorded from patients who underwent cataract surgery using either FLACS (Catalys, LenSx, or Victus) or traditional phacoemulsification technique performed by 3 cornea attendings and 4 cornea fellows. One-way analysis of variance with Bonferroni post hoc tests and unpaired t tests were used to determine the differences between groups. RESULTS: There was no statistically significant difference in cataract grade between groups. NRT was significantly lower only when using the Catalys system compared with the LenSx and Victus platforms and the traditional surgery, in both the attending group (p = 0.006, p = 0.002, p < 0.000, respectively) and the fellow group (p = 0.049, p = 0.038, p = 0.011, respectively). With respect to CDE, there was no significant difference when using the laser systems compared with the traditional surgery in both attending and fellow groups (p > 0.05). NRT and CDE were significantly higher in the fellow group (NRT = 269.10 ± 117.67, CDE = 7.30 ± 4.83) compared with the attending group (NRT = 218.87 ± 109.67, CDE = 5.76 ± 3.66) in traditional cases; however, in FLACS cases, there was no significant difference in NRT and CDE between the fellow group and the attending group. CONCLUSIONS: Inexperienced surgeons seem to require more time and use more ultrasound energy during traditional phacoemulsification when compared with experienced surgeons. The use of FLACS seems to significantly improve the NRT of experienced and inexperienced surgeons.

Outcomes of complex Descemet Stripping Endothelial Keratoplasty performed by cornea fellows.

BACKGROUND: A major obstacle that academic institutions face is the steep learning curve for cornea fellows initially learning to perform Descemet Stripping Endothelial Keratoplasty (DSEK). The purpose of this study is to evaluate the outcomes of complex DSEK performed by cornea fellow supervised by an attending surgeon at an academic institution. METHODS: Patients who underwent a complex DSEK procedure performed by a cornea fellow during the years 2009-2013 were included. All the surgeries were supervised by the same cornea attending. All patients had a minimum follow-up of 6 months. Charts were reviewed for demographic data, intraoperative and postoperative complications and clinical outcomes. Corneal graft survival was calculated using the Kaplan-Meier analysis. RESULTS: Fifty-seven eyes of 55 patients (mean age 77.5 ± 8.5 years) were included in the study with a mean follow-up time of 16.4 ± 15.6 months. Previous graft failure, presence of a tube and history of trabeculectomy were the leading diagnoses to define the surgery as complex. No intraoperative complications occurred. In 21.1% of cases a corneal graft detachment was documented in the first postoperative day. Mean visual acuity improved from 1.06 LogMAR (20/230) preoperatively to 0.39 LogMAR (20/50, p < 0.001) by the sixth postoperative month and to 0.52 LogMAR (20/65, p < 0.001) at the last follow-up visit. Graft failure rate was 29.8%. Kaplan-Meier analysis found a 67.2% graft survival rate at 20 months. CONCLUSIONS: Complex DSEK can be performed successfully with an acceptable postoperative complication rate by cornea fellows during their training period when supervised by an experienced attending.

The Effect of NSAID Pretreatment on Aqueous Humor Prostaglandin E2 Concentration in Eyes Undergoing Femtosecond Laser-Assisted Capsulotomy.

PURPOSE: To assess aqueous humor concentration of prostaglandin E2 (PGE2) after capsulotomy creation using a femtosecond laser (FLAC) in patients pretreated with short-term topical ketorolac versus patients without pretreatment. METHODS: This prospective study comprised consecutive patients scheduled to undergo cataract surgery using a femtosecond laser platform to perform only capsulotomies. An identical protocol for preoperative mydriasis was used for all the eyes included in the study, while aqueous humor was extracted from the anterior chamber of all patients immediately after the initial side port incision. ELISA was performed to quantify aqueous humor PGE2. The patients were divided into 2 groups; in group 1, the patients received short-term topical ketorolac preoperatively, while the patients in group 2 did not receive NSAID pretreatment. RESULTS: Twenty eyes of 20 patients were included in the study (10 eyes in each group). Mean concentration of aqueous humor PGE2 after FLAC was 392.16 ± 162.00 pg/ml and 622.63 ± 331.84 pg/ml for groups 1 and 2, respectively. A statistically significant difference in aqueous humor PGE2 concentration between the two groups (p < 0.05) was demonstrated, with the eyes that received ketorolac pretreatment demonstrating a lower concentration of PGE2. CONCLUSION: Short-term topical use of ketorolac prior to FLAC seems to prevent excessive release of PGE2 in the anterior chamber of the eyes that received NSAID pretreatment when compared to the eyes that did not receive NSAIDs preoperatively.