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A 36-year-old Asian man presented with swelling over the left frontal region involving the upper eyelids, with associated erythema and tenderness for 1 month duration. Clinically he was diagnosed as a case of preseptal cellulitis, however, the lesion did not improve on broad-spectrum systemic antibiotics. CT showed superficial soft tissue swelling in the forehead extending till the superior part of orbit. Histopathological assessment of the lesion revealed clusters of epithelioid cells with multinucleate giant cells in the dermis along with perivascular and periadnexal lymphocytic infiltrates, suggestive of leprosy. The patient was started on oral steroids with multidrug therapy, following which the patient showed early resolution of the lesion within 10 days of treatment. Leprosy is endemic in India, leprosy with reactional episodes mimics other inflammatory and infective etiologies making diagnosis difficult. Leprosy should be present in an ophthalmologist’s diagnostic repertoire while dealing with periorbital swellings for early clinical diagnosis and favourable outcomes.

Microbial keratitis is devastating corneal morbidity with a variable spectrum of clinical manifestations depending on the infective etiology. Irrespective of the varied presentation delayed treatment can lead to severe visual impairment resulting from corneal ulceration, possible perforation, and subsequent scarring. Corticosteroids with a potent anti-inflammatory activity reduce host inflammation, thus minimizing resultant scarring while improving ocular symptoms. These potential effects of corticosteroids have been applied widely to treat various corneal diseases ranging from vernal keratoconjunctivitis to dry eye disease. However, antimicrobial therapy remains the mainstay of treatment in microbial keratitis, whereas the use of adjunctive topical corticosteroid therapy remains a matter of debate. Understandably, the use of topical corticosteroids is a double-edged sword with pros and cons in the treatment of microbial keratitis. Herein we review the rationale for and against the use and safety of topical corticosteroids in the treatment of infective keratitis. Important considerations, including type, dose, efficacy, the timing of initiation of corticosteroids, use of concomitant antimicrobial agents, and duration of corticosteroid therapy while prescribing corticosteroids for microbial keratitis, have been discussed. This review intends to provide new insights into the therapeutic utility of steroids as adjunctive treatment of corneal ulcer.

The early human embryo derived from fusion of an oocyte with a single sperm undergoes growth and differentiation and results in an implantation-ready blastocyst. To initiate implantation, the blastocyst hatches from the zona pellucida, thus making it accessible to external inputs. Our modelling of sperm distribution through the uterus indicates that 200–5000 sperms following natural coitus during mid-luteal phase are in a position of reaching the implantation-stage blastocyst in the maternal uterus. We indeed have ultrastructural evidence of sperm cells intruding into the trophectoderm cells of uterine zona-free blastocysts obtained from rhesus monkeys. The question arises whether the negotiation between additional sperm and azonal blastocyst is a feature of evolution yielding adaptation processes influencing the developmental fate of an individual embryo or a neutral by-product in placental mammals. This process potentially bears implications in pregnancy success, sperm competition, and human health.

This study aimed to review the current literature for epidemiology, pathogenesis, clinical spectrum and management of rhino-orbito-cerebral-mucormycosis (ROCM), especially highlighting the association between ROCM and COVID-19 disease and factors resulting in its resurgence during the pandemic. Mucormycosis is a rare, but an important emerging opportunistic fungal infection, often associated with high morbidity and mortality. ROCM is the commonest and also the most aggressive clinical form occurring in debilitated patients in conjunction with sinus or para-sinus involvement due to the propensity for contiguous spread. Recently ROCM has shown an unprecedented resurgence during the current pandemic. Reports from different parts of the world indicated an increased risk and incidence of ROCM in patients who had required hospital admission and have recovered from moderate-to-severe COVID-19 disease. A majority of mucormycosis cases have been reported from India. The presence of diabetes mellitus (DM) and use of corticosteroids for COVID-19 pneumonia were found to be the key risk factors, resulting in higher mortality. Amidst the ongoing pandemic, with the third wave already having affected most of the world, it becomes imperative to adopt a risk-based approach toward COVID-19 patients predisposed to developing ROCM. This could be based on the most recently published literature and emerging data from centers across the world. The present review intended to elucidate the causes that brought about the current spike in ROCM and the importance of its early detection and management to reduce mortality, loss of eye, and the need for mutilating debridement.

ObjectiveTo evaluate ocular manifestations of reverse transcriptase (RT)-PCR-confirmed SARS-CoV-2-infected patients in a validated comparative model, and additionally to evaluate the correlation between severity of COVID-19 and ocular manifestations.Methods and AnalysisIn a prospective cross-sectional study, a total of 2400 subjects were enrolled over a period of 8 months. To eliminate bias of identical ocular symptom profile in other non-COVID-19 respiratory infections and to acquire a comparative model, 1200 COVID-19 RT-PCR-positive patients (group 1) and 1200 RT-PCR-negative patients (group 2) were included. Data collection included use of a prestructured tool and ‘Google-forms’, along with stratification of patients into ‘mild, moderate, and severe’ categories. Study subjects were evaluated for ocular manifestations by clinical examination and laboratory work-up. Univariate and multivariate logistic regression analyses were performed.Results144 (12%) patients in group 1 had ocular symptoms as compared with 24 (2%) patients in group 2 (pConclusionThe frequency of occurrence of ocular manifestations was higher in group 1 as opposed to group 2. Furthermore, the presence of ocular manifestations carried a direct correlation with severity of systemic disease and presence of comorbidities.

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management. Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021. Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05). Conclusion: : Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.

Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, whole-genome analysis system, to discover new structural variants in a primary MM genome. Through our analysis, we have identified and characterized widespread structural variation in this tumor genome. Additionally, we describe our efforts toward comprehensive characterization of genome structure and variation by integrating our findings from optical mapping with those from DNA sequencing-based genomic analysis. Finally, by studying this MM genome at two time points during tumor progression, we have demonstrated an increase in mutational burden with tumor progression at all length scales of variation.

Latin hypercube designs have been found very useful for designing computer experiments. In recent years, several methods of constructing orthogonal Latin hypercube designs have been proposed in the literature. In this article, we report some more results on the construction of orthogonal Latin hypercubes which result in several new designs.

Although microRNAs (miRNAs) are important regulators of gene expression, the transcriptional regulation of miRNAs themselves is not well understood. We employed an integrative computational pipeline to dissect the transcription factors (TFs) responsible for altered miRNA expression in ovarian carcinoma. Using experimental data and computational predictions to define miRNA promoters across the human genome, we identified TFs with binding sites significantly overrepresented among miRNA genes overexpressed in ovarian carcinoma. This pipeline nominated TFs of the p53/p63/p73 family as candidate drivers of miRNA overexpression. Analysis of data from an independent set of 253 ovarian carcinomas in The Cancer Genome Atlas showed that p73 and p63 expression is significantly correlated with expression of miRNAs whose promoters contain p53/p63/p73 family binding sites. In experimental validation of specific miRNAs predicted by the analysis to be regulated by p73 and p63, we found that p53/p63/p73 family binding sites modulate promoter activity of miRNAs of the miR-200 family, which are known regulators of cancer stem cells and epithelial–mesenchymal transitions. Furthermore, in chromatin immunoprecipitation studies both p73 and p63 directly associated with the miR-200b/a/429 promoter. This study delineates an integrative approach that can be applied to discover transcriptional regulatory mechanisms in other biological settings where analogous genomic data are available.

Variation in genome structure is an important source of human genetic polymorphism: It affects a large proportion of the genome and has a variety of phenotypic consequences relevant to health and disease. In spite of this, human genome structure variation is incompletely characterized due to a lack of approaches for discovering a broad range of structural variants in a global, comprehensive fashion. We addressed this gap with Optical Mapping, a high-throughput, high-resolution single-molecule system for studying genome structure. We used Optical Mapping to create genome-wide restriction maps of a complete hydatidiform mole and three lymphoblast-derived cell lines, and we validated the approach by demonstrating a strong concordance with existing methods. We also describe thousands of new variants with sizes ranging from kb to Mb.

SummaryRecent studies have demonstrated that MyoD initiates a feed-forward regulation of skeletal muscle gene expression, predicting that MyoD binds directly to many genes expressed during differentiation. We have used chromatin immunoprecipitation and high-throughput sequencing to identify genome-wide binding of MyoD in several skeletal muscle cell types. As anticipated, MyoD preferentially binds to a VCASCTG sequence that resembles the in vitro-selected site for a MyoD:E-protein heterodimer, and MyoD binding increases during differentiation at many of the regulatory regions of genes expressed in skeletal muscle. Unanticipated findings were that MyoD was constitutively bound to thousands of additional sites in both myoblasts and myotubes, and that the genome-wide binding of MyoD was associated with regional histone acetylation. Therefore, in addition to regulating muscle gene expression, MyoD binds genome wide and has the ability to broadly alter the epigenome in myoblasts and myotubes.

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5-mo-old), middle-aged (15-mo-old), and old (25-mo-old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 h after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P < 0.01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early response genes (IEGs) found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.

Random matrices whose entries come from a stationary Gaussian process are studied. The limiting behavior of the eigenvalues as the size of the matrix goes to infinity is the main subject of interest in this work. It is shown that the limiting spectral distribution is determined by the absolutely continuous component of the spectral measure of the stationary process, a phenomenon resembling that in the situation where the entries of the matrix are i.i.d. On the other hand, the discrete component contributes to the limiting behavior of the eigenvalues in a completely different way. Therefore, this helps to define a boundary between short and long range dependence of a stationary Gaussian process in the context of random matrices., 50 pages. The current article generalises the results in http://arxiv.org/abs/1304.3394 and gives a new perspective and elegant proofs of some of the results there. It is to appear in Random Matrices: Theory and Applications

Graphics is an important component of data analysis workflows, especially in interactive systems such as R. This chapter gives an overview of R's static graphics facilities. In addition to commonly used functions, we describe the underlying plotting model and how it can be exploited to customize default output. We also give a brief overview of the relatively recent Grid graphics, and the lattice and ggplot2 packages which use it to implement general purpose high-level systems.

Background Solid tumors present a panoply of genomic alterations, from single base changes to the gain or loss of entire chromosomes. Although aberrations at the two extremes of this spectrum are readily defined, comprehensive discernment of the complex and disperse mutational spectrum of cancer genomes remains a significant challenge for current genome analysis platforms. In this context, high throughput, single molecule platforms like Optical Mapping offer a unique perspective. Results Using measurements from large ensembles of individual DNA molecules, we have discovered genomic structural alterations in the solid tumor oligodendroglioma. Over a thousand structural variants were identified in each tumor sample, without any prior hypotheses, and often in genomic regions deemed intractable by other technologies. These findings were then validated by comprehensive comparisons to variants reported in external and internal databases, and by selected experimental corroborations. Alterations range in size from under 5 kb to hundreds of kilobases, and comprise insertions, deletions, inversions and compound events. Candidate mutations were scored at sub-genic resolution and unambiguously reveal structural details at aberrant loci. Conclusions The Optical Mapping system provides a rich description of the complex genomes of solid tumors, including sequence level aberrations, structural alterations and copy number variants that power generation of functional hypotheses for oligodendroglioma genetics.

In this article we show the existence of limiting spectral distribution of a symmetric random matrix whose entries come from a stationary Gaussian process with covariances satisfying a summability condition. We provide an explicit description of the moments of the limiting measure. We also show that in some special cases the Gaussian assumption can be relaxed. The description of the limiting measure can also be made via its Stieltjes transform which is characterized as the solution of a functional equation. In two special cases, we get a description of the limiting measure - one as a free product convolution of two distributions, and the other one as a dilation of the Wigner semicircular law., A minor error in Section 5 corrected. A new section (section 8) is added which generalizes Theorem 7.1. Few other minor changes incorporated

Background Recent advances in automation technologies have enabled the use of flow cytometry for high throughput screening, generating large complex data sets often in clinical trials or drug discovery settings. However, data management and data analysis methods have not advanced sufficiently far from the initial small-scale studies to support modeling in the presence of multiple covariates. Results We developed a set of flexible open source computational tools in the R package flowCore to facilitate the analysis of these complex data. A key component of which is having suitable data structures that support the application of similar operations to a collection of samples or a clinical cohort. In addition, our software constitutes a shared and extensible research platform that enables collaboration between bioinformaticians, computer scientists, statisticians, biologists and clinicians. This platform will foster the development of novel analytic methods for flow cytometry. Conclusion The software has been applied in the analysis of various data sets and its data structures have proven to be highly efficient in capturing and organizing the analytic work flow. Finally, a number of additional Bioconductor packages successfully build on the infrastructure provided by flowCore, open new avenues for flow data analysis.

Flow cytometry (FCM) has become an important analysis technology in health care and medical research, but the large volume of data produced by modern high-throughput experiments has presented significant new challenges for computational analysis tools. The development of an FCM software suite in Bioconductor represents one approach to overcome these challenges. In the spirit of the R programming language (Tree Star Inc., “FlowJo”), these tools are predominantly console-driven, allowing for programmatic access and rapid development of novel algorithms. Using this software requires a solid understanding of programming concepts and of the R language. However, some of these tools|in particular the statistical graphics and novel analytical methods|are also useful for nonprogrammers. To this end, we have developed an open source, extensible graphical user interface (GUI) iFlow, which sits on top of the Bioconductor backbone, enabling basic analyses by means of convenient graphical menus and wizards. We envision iFlow to be easily extensible in order to quickly integrate novel methodological developments.

Summary: Automated analysis of flow cytometry (FCM) data is essential for it to become successful as a high throughput technology. We believe that the principles of Trellis graphics can be adapted to provide useful visualizations that can aid such automation. In this article, we describe the R/Bioconductor package flowViz that implements such visualizations. Availability: flowViz is available as an R package from the Bioconductor project: http://bioconductor.org Contact: dsarkar@fhcrc.org

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5 months old), middle-aged (15 months old), and old (25 months old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 hours after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P

SUMMARY Mixture modeling provides an effective approach to the differential expression problem in microarray data analysis. Methods based on fully parametric mixture models are available, but lack of fit in some examples indicates that more flexible models may be beneficial. Existing, more flexible, mixture models work at the level of one-dimensional gene-specific summary statistics, and so when there are relatively few measurements per gene these methods may not provide sensitive detectors of differential expression. We propose a hierarchical mixture model to provide methodology that is both sensitive in detecting differential expression and sufficiently flexible to account for the complex variability of normalized microarray data. EM-based algorithms are used to fit both parametric and semiparametric versions of the model. We restrict attention to the two-sample comparison problem; an experiment involving Affymetrix microarrays and yeast translation provides the motivating case study. Gene-specific posterior probabilities of differential expression form the basis of statistical inference; they define short gene lists and false discovery rates. Compared to several competing methodologies, the proposed methodology exhibits good operating characteristics in a simulation study, on the analysis of spike-in data, and in a cross-validation calculation.