Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections.

We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All patients received remdesivir and some also received nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient treated with remdesivir and nirmatrelvir-ritonavir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.

Clinical and Technical Outcomes of Intracranial-Intracranial Bypass for Treating Complex Intracranial Aneurysms: An Analysis of 255 Patients.

BACKGROUND: Despite the recent increase in publications centered on intracranial-intracranial (IC-IC) bypasses for complex aneurysms, there is no systematic evidence regarding their outcomes. The purpose was to assess the outcomes of patients subjected to IC-IC bypass for aneurysms. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, a systematic review was conducted. Criteria for inclusion entailed studies with a cohort of at least 4 patients having undergone IC-IC bypass for aneurysms, detailing at least one outcome, such as patency, clinical outcomes, complications, and procedure-related mortality. When the study included patients who had undergone extracranial-intracranial (EC-IC) bypass, the authors extracted the patency and clinical data to juxtapose them with the results of IC-IC. RESULTS: Of the 2509 shortlisted studies, 22 met our inclusion criteria, encompassing 255 patients and 263 IC-IC bypass procedures. The IC-IC bypass procedure exhibited a patency rate of 93% (95% confidence interval [CI]: 89%-95%). The patency rate of IC-IC and EC-IC bypasses did not significantly differ (odds ratio=0.60 [95% CI: 0.18-1.96]). Concerning clinical outcomes, 91% of the IC-IC patients had positive results (95% CI: 85%-97%), with no significant disparity between the IC-IC and EC-IC groups (odds ratio=1.29 [95% CI: 0.43-3.88]). After analysis, the complication rate was 11% (95% CI: 5%-18%). Procedure-related mortality was 1% (95% CI: 0%-4%). CONCLUSIONS: IC-IC bypass is valuable for the treatment of complex intracranial aneurysms, boasting high patency and positive clinical outcomes. Complications are unusual, and procedure-related mortality is minimal. Comparing IC-IC and EC-IC led to no significant differences.

Fractal structures in the chaotic advection of passive scalars in leaky planar hydrodynamical flows.

The advection of passive scalars in time-independent two-dimensional incompressible fluid flows is an integrable Hamiltonian system. It becomes non-integrable if the corresponding stream function depends explicitly on time, allowing the possibility of chaotic advection of particles. We consider for a specific model (double gyre flow), a given number of exits through which advected particles can leak, without disturbing the flow itself. We investigate fractal escape basins in this problem and characterize fractality by computing the uncertainty exponent and basin entropy. Furthermore, we observe the presence of basin boundaries with points exhibiting the Wada property, i.e., boundary points that separate three or more escape basins.

Identification of an Immunodominant B-Cell Epitope in African Swine Fever Virus p30 Protein and Evidence of p30 Antibody-Mediated Antibody Dependent Cellular Cytotoxicity.

African Swine Fever Virus (ASFV) is a large dsDNA virus that encodes at least 150 proteins. The complexity of ASFV and lack of knowledge of effector immune functions and protective antigens have hindered the development of safe and effective ASF vaccines. In this study, we constructed four Orf virus recombinant vectors expressing individual ASFV genes B602L, -CP204L, E184L, and -I73R (ORFVΔ121-ASFV-B602L, -CP204L, -E184L, and -I73R). All recombinant viruses expressed the heterologous ASFV proteins in vitro. We then evaluated the immunogenicity of the recombinants by immunizing four-week-old piglets. In two independent animal studies, we observed high antibody titers against ASFV p30, encoded by CP204L gene. Using Pepscan ELISA, we identified a linear B-cell epitope of 12 amino acids in length (Peptide 15) located in an exposed loop region of p30 as an immunodominant ASFV epitope. Additionally, antibodies elicited against ASFV p30 presented antibody-dependent cellular cytotoxicity (ADCC) activity. These results underscore the role of p30 on antibody responses elicited against ASFV and highlight an important functional epitope that contributes to p30-specific antibody responses.

Posterior Inferior Cerebellar Artery-Posterior Inferior Cerebellar Artery Bypass versus Occipital Artery-Posterior Inferior Cerebellar Artery Bypass for Treating Posterior Circulation Aneurysms: A Systematic Review and Comparative Meta-Analysis.

BACKGROUND: When traditional therapies are unsuitable, revascularization becomes essential for managing posterior inferior cerebellar artery (PICA) or vertebral artery aneurysms. Notably, the PICA-PICA bypass has emerged as a promising option, overshadowing the occipital artery-PICA (OA-PICA) bypass. The objective was to compare the safety and efficacy of OA-PICA and PICA-PICA bypasses. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we conducted a systematic review and meta-analysis to evaluate the safety and efficacy of OA-PICA and PICA-PICA bypasses for treating posterior circulation aneurysms. RESULTS: We analyzed 13 studies for the PICA-PICA bypass and 16 studies on the OA-PICA bypass, involving 84 and 110 patients, respectively. The median average follow-up for PICA-PICA bypass was 8 months (2-50.3 months), while for OA-PICA, it was 27.8 months (6-84 months). The patency rate for OA-PICA was 97% (95% confidence interval [CI]: 92%-100%) and 100% (95% CI: 95%-100%) for PICA-PICA. Complication rates were 29% (95% CI: 10%-47%) for OA-PICA and 12% (95% CI: 3%-21%) for PICA-PICA. Good clinical outcomes were observed in 71% (95% CI: 52%-90%) of OA-PICA patients and 87% (95% CI: 75%-100%) of PICA-PICA patients. Procedure-related mortality was 1% (95% CI: 0%-6%) for OA-PICA and 1% (95% CI: 0%-10%) for PICA-PICA. CONCLUSIONS: Both procedures have demonstrated promising results in efficacy and safety. PICA-PICA exhibits slightly better patency rates, better clinical outcomes, and fewer complications, but with a lack of substantial follow-up and a smaller sample size. The choice between these procedures should be based on the surgeon's expertise and the patient's anatomy.

Tuning Molecular Motion Enhances Intrinsic Fluorescence in Peptide Amphiphile Nanofibers.

Peptide amphiphiles (PAs) are highly tunable molecules that were recently found to exhibit aggregation-induced emission (AIE) when they self-assemble into nanofibers. Here, we leverage decades of molecular design and self-assembly study of PAs to strategically tune their molecular motion within nanofibers to enhance AIE, making them a highly useful platform for applications such as sensing, bioimaging, or materials property characterization. Since AIE increases when aggregated molecules are rigidly and closely packed, we altered the four most closely packed amino acids nearest to the hydrophobic core by varying the order and composition of glycine, alanine, and valine pairs. Of the six PA designs studied, C16VVAAK2 had the highest quantum yield at 0.17, which is a more than 10-fold increase from other PA designs including the very similar C16AAVVK2, highlighting the importance of precise amino acid placement to anchor rigidity closest to the core. We also altered temperature to increase AIE. C16VVAAK2 exhibited an additional 4-fold increase in maximum fluorescence intensity when the temperature was raised from 5 to 65 °C. As the temperature increased, the secondary structure transitioned from ß-sheet to random coil, indicating that further packing an already aligned molecular system makes it even more readily able to transfer energy between the electron-rich amides. This work both unveils a highly fluorescent AIE PA system design and sheds insights into the molecular orientation and packing design traits that can significantly enhance AIE in self-assembling systems.

Antioxidants in Photoaging: From Molecular Insights to Clinical Applications.

Photoaging (PA) is considered a silent disease affecting millions of people globally and is defined as skin damage due to prolonged exposure to ultraviolet radiation (UVR) from the sun. Physiologically, the skin is in a state of renewal and synthesis of components of the extracellular matrix (ECM). However, exposure to UVR affects the production of the ECM, and the functioning and response of skin cells to UVR begins to change, thus expressing clinical and phenotypic characteristics of PA. The primary mechanisms involved in PA are direct damage to the DNA of skin cells, increases in oxidative stress, the activation of cell signaling pathways responsible for the loss of skin integrity, and cytotoxicity. The medical and scientific community has been researching new therapeutic tools that counteract PA, considering that the damage caused by UVR exceeds the antioxidant defense mechanisms of the skin. Thus, in recent years, certain nutraceuticals and phytochemicals have been found to exhibit potential antioxidant and photoprotective effects. Therefore, the main objective of this review is to elucidate the molecular bases of PA and the latest pharmaceutical industry findings on antioxidant treatment against the progression of PA.

Surface-enhanced Raman Spectroscopy in urinalysis of hypertension patients with kidney disease.

Arterial hypertension (AH) is a multifactorial and asymptomatic disease that affects vital organs such as the kidneys and heart. Considering its prevalence and the associated severe health repercussions, hypertension has become a disease of great relevance for public health across the globe. Conventionally, the classification of an individual as hypertensive or non-hypertensive is conducted through ambulatory blood pressure monitoring over a 24-h period. Although this method provides a reliable diagnosis, it has notable limitations, such as additional costs, intolerance experienced by some patients, and interferences derived from physical activities. Moreover, some patients with significant renal impairment may not present proteinuria. Accordingly, alternative methodologies are applied for the classification of individuals as hypertensive or non-hypertensive, such as the detection of metabolites in urine samples through liquid chromatography or mass spectrometry. However, the high cost of these techniques limits their applicability for clinical use. Consequently, an alternative methodology was developed for the detection of molecular patterns in urine collected from hypertension patients. This study generated a direct discrimination model for hypertensive and non-hypertensive individuals through the amplification of Raman signals in urine samples based on gold nanoparticles and supported by chemometric techniques such as partial least squares-discriminant analysis (PLS-DA). Specifically, 162 patient urine samples were used to create a PLS-DA model. These samples included 87 urine samples from patients diagnosed with hypertension and 75 samples from non-hypertensive volunteers. In the AH group, 35 patients were diagnosed with kidney damage and were further classified into a subgroup termed (RAH). The PLS-DA model with 4 latent variables (LV) was used to classify the hypertensive patients with external validation prediction (P) sensitivity of 86.4%, P specificity of 77.8%, and P accuracy of 82.5%. This study demonstrates the ability of surface-enhanced Raman spectroscopy to differentiate between hypertensive and non-hypertensive patients through urine samples, representing a significant advance in the detection and management of AH. Additionally, the same model was then used to discriminate only patients diagnosed with renal damage and controls with a P sensitivity of 100%, P specificity of 77.8%, and P accuracy of 82.5%.

Performance of ChatGPT on the Brazilian Radiology and Diagnostic Imaging and Mammography Board Examinations.

This prospective exploratory study conducted from January 2023 through May 2023 evaluated the ability of ChatGPT to answer questions from Brazilian radiology board examinations, exploring how different prompt strategies can influence performance using GPT-3.5 and GPT-4. Three multiple-choice board examinations that did not include image-based questions were evaluated: (a) radiology and diagnostic imaging, (b) mammography, and (c) neuroradiology. Five different styles of zero-shot prompting were tested: (a) raw question, (b) brief instruction, (c) long instruction, (d) chain-of-thought, and (e) question-specific automatic prompt generation (QAPG). The QAPG and brief instruction prompt strategies performed best for all examinations (P < .05), obtaining passing scores (≥60%) on the radiology and diagnostic imaging examination when testing both versions of ChatGPT. The QAPG style achieved a score of 60% for the mammography examination using GPT-3.5 and 76% using GPT-4. GPT-4 achieved a score up to 65% in the neuroradiology examination. The long instruction style consistently underperformed, implying that excessive detail might harm performance. GPT-4's scores were less sensitive to prompt style changes. The QAPG prompt style showed a high volume of the "A" option but no statistical difference, suggesting bias was found. GPT-4 passed all three radiology board examinations, and GPT-3.5 passed two of three examinations when using an optimal prompt style. Keywords: ChatGPT, Artificial Intelligence, Board Examinations, Radiology and Diagnostic Imaging, Mammography, Neuroradiology © RSNA, 2023 See also the commentary by Trivedi and Gichoya in this issue.

Maxillary artery utilization in subcranial-intracranial bypass procedures: a comprehensive systematic review and pooled analysis.

The utilization of the internal maxillary artery (IMAX) in subcranial-intracranial bypass for revascularization in complex aneurysms, tumors, or refractory ischemia shows promise. However, robust evidence concerning its outcomes is lacking. Hence, the authors embarked on a systematic review with pooled analysis to elucidate the efficacy of this approach. We systematically searched PubMed, Embase, and Web of Science databases following PRISMA guidelines. Included articles used the IMAX as a donor vessel for revascularizing an intracranial area and reported at least one of the following outcomes: patency, complications, or clinical data. Favorable outcomes were defined as the absence of neurologic deficits or improvement in the baseline condition. Complications were considered any adverse event directly related to the procedure. Out of 418 retrieved articles, 26 were included, involving 183 patients. Among them, 119 had aneurysms, 41 experienced ischemic strokes (transient or not), 2 had arterial occlusions, and 3 had neoplasia. Furthermore, 91.8% of bypasses used radial artery grafts, and 87.9% revascularized the middle cerebral artery territory. The median average follow-up period was 12 months (0.3-53.1). The post-operation patency rate was 99% (95% CI: 97-100%; I2=0%), while the patency rate at follow-up was 82% (95% CI: 68-96%; I2=77%). Complications occurred in 21% of cases (95% CI: 9-32%; I2=58%), with no significant procedure-related mortality in 0% (95% CI: 0-2%; I2=0%). Favorable outcomes were observed in 88% of patients (95% CI: 81-96%; I2=0%), and only 3% experienced ischemia (95% CI: 0-6%; I2=0%). The subcranial-intracranial bypass with the IMAX shows excellent postoperative patency and considerable favorable clinical outcomes. While complications exist, the procedure carries a minimal risk of mortality. However, long-term patency presents heterogeneous findings, warranting additional research.

Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock.

DNA methylation (DNAm)-based age clocks have been studied extensively as a biomarker of human ageing and a risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly; however, this claim was drawn from a single clock using a relatively small sample size and so warrants further investigation. We collected the largest cerebellum DNAm dataset (N = 752) to date. We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population (N = 404). From the 613 cerebellum age-associated CpGs, we built a highly accurate age prediction model for the cerebellum named CerebellumClockspecific (Pearson correlation=0.941, MAD=3.18 years). Ageing rate comparisons based on the two tissue-specific clocks constructed on the 201 overlapping age-associated CpGs support the cerebellum has younger DNAm age. Nevertheless, we built BrainCortexClock to prove a single DNAm clock is able to unbiasedly estimate DNAm ages of both cerebellum and cerebral cortex, when they are adequately and equally represented in the training dataset. Comparing ageing rates across tissues using DNA methylation multi-tissue clocks is flawed. The large underestimation of age prediction for cerebellums by previous clocks mainly reflects the improper usage of these age clocks. There exist strong and consistent ageing effects on the cerebellar methylome, and we suggest the smaller number of age-associated CpG sites in cerebellum is largely attributed to its extremely low average cell replication rates.

Clinical characteristics of probands with obsessive-compulsive disorder from simplex and multiplex families.

Genetic and non-genetic factors contribute to obsessive-compulsive disorder (OCD), with strong evidence of familial clustering. Genomic studies in psychiatry have used the concepts of families that are "simplex" (one affected) versus "multiplex" (multiple affected). Our study compares demographic and clinical data from OCD probands in simplex and multiplex families to uncover potential differences. We analyzed 994 OCD probands (501 multiplex, 493 simplex) from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders (C-TOC). Clinicians administered the Structured Clinical Interview for DSM-IV (SCID-IV) to diagnose, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess severity, and Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) to assess symptom dimensionality. Demographics, clinical history, and family data were collected. Compared to simplex probands, multiplex probands had earlier onset, higher sexual/religious and hoarding dimensions severity, increased comorbidity with other obsessive-compulsive-related disorders (OCRD), and higher family history of psychiatric disorders. These comparisons provide the first insights into demographic and clinical differences between Latin American simplex and multiplex families with OCD. Distinct clinical patterns may suggest diverse genetic and environmental influences. Further research is needed to clarify these differences, which have implications for symptom monitoring and management.

Dietary Vitamin D Mitigates Coronavirus-Induced Lung Inflammation and Damage in Mice.

The COVID-19 pandemic caused by the SARS-CoV-2 (ß-CoV) betacoronavirus has posed a significant threat to global health. Despite the availability of vaccines, the virus continues to spread, and there is a need for alternative strategies to alleviate its impact. Vitamin D, a secosteroid hormone best known for its role in bone health, exhibits immunomodulatory effects in certain viral infections. Here, we have shown that bioactive vitamin D (calcitriol) limits in vitro replication of SARS-CoV-2 and murine coronaviruses MHV-3 and MHV-A59. Comparative studies involving wild-type mice intranasally infected with MHV-3, a model for studying ß-CoV respiratory infections, confirmed the protective effect of vitamin D in vivo. Accordingly, mice fed a standard diet rapidly succumbed to MHV-3 infection, whereas those on a vitamin D-rich diet (10,000 IU of Vitamin D3/kg) displayed increased resistance to acute respiratory damage and systemic complications. Consistent with these findings, the vitamin D-supplemented group exhibited lower viral titers in their lungs and reduced levels of TNF, IL-6, IL-1ß, and IFN-γ, alongside an enhanced type I interferon response. Altogether, our findings suggest vitamin D supplementation ameliorates ß-CoV-triggered respiratory illness and systemic complications in mice, likely via modulation of the host's immune response to the virus.

Ventriculoatrial Shunt Versus Ventriculoperitoneal Shunt: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) is usually the primary choice for cerebrospinal fluid shunting for most neurosurgeons, while ventriculoatrial shunt (VAS) is a second-line procedure because of historical complications. Remarkably, there is no robust evidence claiming the superiority of VPS over VAS. Thus, we aimed to compare both procedures through a meta-analysis. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, the authors systematically searched the literature for articles comparing VAS with VPS. The included articles had to detail one of the following outcomes: revisions, infections, shunt-related mortality, or complications. In addition, the cohort for each shunt model had to encompass more than 4 patients. RESULTS: Of 1872 articles, 16 met our criteria, involving 4304 patients, with 1619 undergoing VAS and 2685 receiving VPS placement. Analysis of revision surgeries showed no significant difference between VAS and VPS (risk ratio [RR] = 1.10, 95% CI: 0.9-1.34; I2 = 84%, random effects). Regarding infections, the analysis also found no significant difference between the groups (RR = 0.67, 95% CI: 0.36-1.25; I2 = 74%, random effects). There was no statistically significant disparity between both methods concerning shunt-related deaths (RR = 2.11, 95% CI: 0.68-6.60; I2 = 56%, random effects). Included studies after 2000 showed no VAS led to cardiopulmonary complications, and only 1 shunt-related death could be identified. CONCLUSION: Both methods show no significant differences in procedure revisions, infections, and shunt-related mortality. The literature is outdated, research in adults is lacking, and future randomized studies are crucial to understand the profile of VAS when comparing it with VPS. The final decision on which distal site for cerebrospinal shunting to use should be based on the patient's characteristics and the surgeon's expertise.

Chloroplast genome assembly of Serjania erecta Raldk: comparative analysis reveals gene number variation and selection in protein-coding plastid genes of Sapindaceae.

Serjania erecta Raldk is an essential genetic resource due to its anti-inflammatory, gastric protection, and anti-Alzheimer properties. However, the genetic and evolutionary aspects of the species remain poorly known. Here, we sequenced and assembled the complete chloroplast genome of S. erecta and used it in a comparative analysis within the Sapindaceae family. S. erecta has a chloroplast genome (cpDNA) of 159,297 bp, divided into a Large Single Copy region (LSC) of 84,556 bp and a Small Single Copy region (SSC) of 18,057 bp that are surrounded by two Inverted Repeat regions (IRa and IRb) of 28,342 bp. Among the 12 species used in the comparative analysis, S. erecta has the fewest long and microsatellite repeats. The genome structure of Sapindaceae species is relatively conserved; the number of genes varies from 128 to 132 genes, and this variation is associated with three main factors: (1) Expansion and retraction events in the size of the IRs, resulting in variations in the number of rpl22, rps19, and rps3 genes; (2) Pseudogenization of the rps2 gene; and (3) Loss or duplication of genes encoding tRNAs, associated with the duplication of trnH-GUG in X. sorbifolium and the absence of trnT-CGU in the Dodonaeoideae subfamily. We identified 10 and 11 mutational hotspots for Sapindaceae and Sapindoideae, respectively, and identified six highly diverse regions (tRNA-Lys - rps16, ndhC - tRNA-Val, petA - psbJ, ndhF, rpl32 - ccsA, and ycf1) are found in both groups, which show potential for the development of DNA barcode markers for molecular taxonomic identification of Serjania. We identified that the psaI gene evolves under neutrality in Sapindaceae, while all other chloroplast genes are under strong negative selection. However, local positive selection exists in the ndhF, rpoC2, ycf1, and ycf2 genes. The genes ndhF and ycf1 also present high nucleotide diversity and local positive selection, demonstrating significant potential as markers. Our findings include providing the first chloroplast genome of a member of the Paullinieae tribe. Furthermore, we identified patterns in variations in the number of genes and selection in genes possibly associated with the family's evolutionary history.