Muneeb Ahmad Faiq

The existence of a previously unrecognized subarachnoid lymphatic‐like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details.

Background: Emergence of the new SARS-CoV-2 variant B.1.1.529 worried health policy makers worldwide due to a large number of mutations in its genomic sequence, especially in the spike protein region. The World Health Organization (WHO) designated this variant as a global variant of concern (VOC), which was named “Omicron.” Following Omicron’s emergence, a surge of new COVID-19 cases was reported globally, primarily in South Africa. Objective: The aim of this study was to understand whether Omicron had an epidemiological advantage over existing variants. Methods: We performed an in silico analysis of the complete genomic sequences of Omicron available on the Global Initiative on Sharing Avian Influenza Data (GISAID) database to analyze the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period from October 1 to November 29, 2021) with matched epidemiological data (new COVID-19 cases and deaths) from South Africa. Results: Compared with the current list of global VOCs/variants of interest (VOIs), as per the WHO, Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with the Alpha variant for the complete sequence and the RBM. The mutations were found to be primarily condensed in the spike region (n=28-48) of the virus. Further mutational analysis showed enrichment for the mutations decreasing binding affinity to angiotensin-converting enzyme 2 receptor and receptor-binding domain protein expression, and for increasing the propensity of immune escape. An inverse correlation of Omicron with the Delta variant was noted (r=–0.99, P<.001; 95% CI –0.99 to –0.97) in the sequences reported from South Africa postemergence of the new variant, subsequently showing a decrease. There was a steep rise in new COVID-19 cases in parallel with the increase in the proportion of Omicron isolates since the report of the first case (74%-100%). By contrast, the incidence of new deaths did not increase (r=–0.04, P>.05; 95% CI –0.52 to 0.58). Conclusions: In silico analysis of viral genomic sequences suggests that the Omicron variant has more remarkable immune-escape ability than existing VOCs/VOIs, including Delta, but reduced virulence/lethality than other reported variants. The higher power for immune escape for Omicron was a likely reason for the resurgence in COVID-19 cases and its rapid rise as the globally dominant strain. Being more infectious but less lethal than the existing variants, Omicron could have plausibly led to widespread unnoticed new, repeated, and vaccine breakthrough infections, raising the population-level immunity barrier against the emergence of new lethal variants. The Omicron variant could have thus paved the way for the end of the pandemic.

Background: A newly emerged SARS-CoV-2 variant B.1.1.529 has worried the health policy makers worldwide due to the presence of a large number of mutations in its genomic sequence, especially in the spike protein region. World Health Organization (WHO) has designated it as a global variant of concern (VOC) and has named as ‘Omicron’. A surge in new COVID-19 cases have been reported from certain geographical locations, primarily in South Africa (SA) following the emergence of Omicron. Materials and methods: We performed an in silico analysis of the complete genomic sequences of Omicron available on GISAID (until 2021-12-10) to predict the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. The mutations present at the receptor binding domain (RBD) of the variants were assessed using an open analysis pipeline which integrates a yeast-display platform with deep mutational scanning. Further, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period of 01 Oct-10 ^th Dec, 2021) with the current epidemiological data (new COVID-19 cases and deaths) from SA to understand whether the Omicron has an epidemiological advantage over existing variants. Results: Compared to the current list of global VOCs/VOIs (as per WHO) Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with Alpha variant for the complete sequence as well as for RBM. The mutations were found primarily condensed in spike region (28-48) of the virus. Further, the mutational analysis showed enrichment for the mutations decreasing ACE2-binding affinity and RBD protein expression, in contrast, increasing the propensity of immune escape. An inverse correlation of Omicron with Delta variant was noted (r=-0.99, p< .001, 95% CI: -0.99 to - 0.97) in the sequences reported from SA post-emergence of the new variant, later showing a decrease. There has been a steep rise in the new COVID-19 cases in parallel with increase in the proportion of Omicron since the first case (74-100%), on the contrary, the incidences of new deaths have not been increased (r=-0.04, p>0.05, 95% CI =-0.52 to 0.58). Conclusions: Omicron may have greater immune escape ability than the existing VOCs/VOIs. However, there are no clear indications coming out from the predictive mutational analysis that the Omicron may have higher virulence/lethality than other variants, including Delta. The higher ability for immune escape may be a likely reason for the recent surge in Omicron cases in SA. Highlights: Higher immune escape ability than the existing VOCs/VOIs No clear indications of increased affinity for ACE2 binding Driving a new COVID-19 wave in South Africa Outcompeting Delta variant Currently, no clear evidence for increased virulence/lethality

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS‐CoV‐2 variants have key mutations that can induce significant changes in the virus‐host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor‐binding domain (RBD) of the viral spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor in the host‐cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host‐cell entry and the replication of the virus. The putative changes in the virus–host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS‐CoV‐2 infection and the disease outcomes are known to be influenced by host‐cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entry‐receptor and the associated proteases, can have more efficient host‐cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue‐injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine‐acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.

The paucity of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐specific virulence factors has greatly hampered the therapeutic management of patients with coronavirus disease 2019 (COVID‐19). Recently, a cluster of studies appeared, which presented empirical evidence for SARS‐CoV‐2‐specific virulence factors that can explain key elements of COVID‐19 pathology. These studies unravel multiple structural and nonstructural specifics of SARS‐CoV‐2, such as a unique FURIN cleavage site, papain‐like protease (SCoV2‐PLpro), ORF3b and nonstructural proteins, and dynamic conformational changes in the structure of spike protein during host cell fusion, which give it an edge in infectivity and virulence over previous coronaviruses causing pandemics. Investigators provided robust evidence that SARS‐CoV‐2‐specific virulence factors may have an impact on viral infectivity and transmissibility and disease severity as well as the development of immunity against the infection, including response to the vaccines. In this article, we are presenting a summarized account of the newly reported studies.

The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft‐tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system.Level of Evidence 3: Technical Efficacy Stage 3:

Manifestation of neurological symptoms in certain patients of coronavirus disease‐2019 (COVID‐19) has warranted for their virus‐induced etiogenesis. SARS‐CoV‐2, the causative agent of COVID‐19, belongs to the genus of betacoronaviruses which also includes SARS‐CoV‐1 and MERS‐CoV; causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS‐CoV‐2 in vivo are still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature. Based on the recent evidence for the presence of SARS‐CoV‐2 host cell entry receptors in specific components of the human nervous and vascular tissue, a neural (olfactory and/or vagal), and a hematogenous—crossing the blood–brain barrier, routes have been proposed. The neurological symptoms in COVID‐19 may also arise as a consequence of the “cytokine storm” (characteristically present in severe disease) induced neuroinflammation, or co‐morbidities. There is also a possibility that, there may be multiple routes of SARS‐CoV‐2 entry into the brain, or multiple mechanisms can be involved in the pathogenesis of the neurological symptoms. In this review article, we have discussed the possible routes of SARS‐CoV‐2 brain entry based on the emerging evidence for this virus, and that available for other betacoronaviruses in literature.

DNA damage, largely owing to oxidative stress, is a leading cause of defective sperm function. High levels of oxidative stress result in damage to sperm DNA, RNA transcripts, and telomeres and, therefore might provide a common underlying aetiology of male infertility and recurrent pregnancy loss, in addition to congenital malformations, complex neuropsychiatric disorders, and childhood cancers in children fathered by men with defective sperm cells. Spermatozoa are highly vulnerable to oxidative stress owing to limited levels of antioxidant defence and a single, limited DNA-damage detection and repair mechanism. Oxidative stress is predominantly caused by a host of lifestyle-related factors, the majority of which are modifiable. Antioxidant regimens and lifestyle modifications could both be plausible therapeutic approaches that enable the burden of oxidative-stress-induced male factor infertility to be overcome. Lifestyle interventions including yoga and meditation can substantially improve the integrity of sperm DNA by reducing levels of oxidative DNA damage, regulating oxidative stress and by increasing the expression of genes responsible for DNA repair, cell-cycle control and anti-inflammatory effects. Oxidative stress is caused by various modifiable factors, and the use of simple interventions can decrease levels of oxidative stress, and therefore reduce the incidence of both infertility and complex diseases in the resultant offspring.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10⁻¹⁵), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10⁻¹⁶), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10⁻¹⁴), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10⁻¹¹), and DPM2–FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10⁻¹²). We also confirmed significant association at three previously described loci (P < 5 × 10⁻⁸ for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1–ST18)¹, providing new insights into the biology of PACG.