Clonal expansion and rapid characterization of Klebsiella pneumoniae ST1788, an otherwise uncommon strain spreading in Wales, UK.

A multidrug-resistant strain of Klebsiella pneumoniae (Kp) sequence type (ST) 1788, an otherwise uncommon ST worldwide, was isolated from 65 patients at 11 hospitals and 11 general practices across South and West Wales, UK, between February 2019 and November 2021. A collection of 97 Kp ST1788 isolates (including 94 from Wales) was analysed to investigate the diversity and spread across Wales and to identify molecular marker(s) to aid development of a strain-specific real-time PCR. Whole genome sequencing (WGS) was performed with Illumina technology and the data were used to perform phylogenetic analyses. Pan-genome analysis of further Kp genome collections was used to identify an ST1788-specific gene target; a real-time PCR was then validated against a panel of 314 strains and 218 broth-enriched screening samples. Low genomic diversity was demonstrated amongst the 94 isolates from Wales. Evidence of spread within and across healthcare facilities was found. A yersiniabactin locus and the KL2 capsular locus were identified in 85/94 (90.4 %) and 94/94 (100 %) genomes respectively; bla SHV-232, bla TEM-1, bla CTX-M-15 and bla OXA-1 were simultaneously carried by 86/94 (91.5 %) isolates; 4/94 (4.3 %) isolates also carried bla OXA-48 carbapenemase. Aminoglycoside and fluoroquinolone resistance markers were found in 94/94 (100 %) and 86/94 (91.5 %) isolates respectively. The ST1788-specific real-time PCR was 100 % sensitive and specific. Our analyses demonstrated recent clonal expansion and spread of Kp ST1788 in the community and across healthcare facilities in South and West Wales with isolates carrying well-defined antimicrobial resistance and virulence markers. An ST1788-specific marker was also identified, enabling rapid and reliable preliminary characterization of isolates by real-time PCR. This study confirms the utility of WGS in investigating novel strains and in aiding proactive implementation of molecular tools to assist infection control specialists.

Epidemiological analysis of the first 1000 cases of SARS-CoV-2 lineage BA.1 (B.1.1.529, Omicron) compared with co-circulating Delta in Wales, UK.

BACKGROUND: The Omicron (lineage B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wales, UK, on 3 December 2021. The aim of the study was to describe the first 1000 cases of the Omicron variant by demographic, vaccination status, travel and severe outcome status and compare this to contemporaneous cases of the Delta variant. METHODS: Testing, typing and contact tracing data were collected by Public Health Wales and analysis undertaken by the Communicable Disease Surveillance Centre (CDSC). Risk ratios for demographic factors and symptoms were calculated comparing Omicron cases to Delta cases identified over the same time period. RESULTS: By 14 December 2021, 1000 cases of the Omicron variant had been identified in Wales. Of the first 1000, just 3% of cases had a prior history of travel revealing rapid community transmission. A higher proportion of Omicron cases were identified in individuals aged 20-39, and most cases were double vaccinated (65.9%) or boosted (15.7%). Age-adjusted analysis also revealed that Omicron cases were less likely to be hospitalised (0.4%) or report symptoms (60.8%). Specifically a significant reduction was observed in the proportion of Omicron cases reporting anosmia (8.9%). CONCLUSION: Key findings include a lower risk of anosmia and a reduced risk of hospitalisation in the first 1000 Omicron cases compared with co-circulating Delta cases. We also identify that existing measures for travel restrictions to control importations of new variants identified outside the United Kingdom did not prevent the rapid ingress of Omicron within Wales.

Corneal Endothelial Dysfunction as a Manifestation of Digoxin Toxicity.

PURPOSE: The purpose of this study was to report a case of corneal endothelial dysfunction and subsequent corneal edema in a patient with digoxin toxicity. METHOD: This was a case report. RESULTS: A 77-year-old woman diagnosed with open-angle glaucoma and treated with a topical prostaglandin analog for 5 years developed blurred vision and photopsia in both eyes. Systemic medications included digoxin, furosemide, apixaban, amlodipine, enalapril, and simvastatin. Ocular examination revealed folds in Descemet membrane and corneal stromal edema in both eyes, with normal fundoscopy. Ancillary tests revealed elevated serum digoxin levels. No intervention other than discontinuation of digoxin was initiated. The corneal edema improved after that and resolved in the next 2 weeks. CONCLUSIONS: We encountered 1 case of corneal edema secondary to corneal endothelial dysfunction in a patient with digoxin toxicity. Special care should be taken to elicit a complete history because ocular signs can be manifestations of systemic alterations with vital importance for patients.

CLIMB-COVID: continuous integration supporting decentralised sequencing for SARS-CoV-2 genomic surveillance.

In response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network.

Prospective Evaluation of the First Mitomycin C Augmented Needle Revision in Patients With Failed Nonpenetrating Deep Sclerectomy.

PRECIS: At 6 months the procedure achieved a 33.89% drop in intraocular pressure (IOP), had an overall success rate of 57.15%, and did not change the best-corrected visual acuity. Achieving <8 mm Hg of IOP the day after the procedure may be a prognostic success indicator. PURPOSE: The purpose of this study was to evaluate the first mitomycin C (MMC)-augmented needle revision in patients with failed nonpenetrating deep sclerectomy (NPDS) and factors associated with its success. MATERIALS AND METHODS: This prospective, nonrandomized comparative trial included 21 consecutive patients (21 eyes) who underwent their first MMC needling revision of failed NPDS blebs. The success was defined as absolute if the IOP decreased >20% from the preoperative value without antiglaucoma treatment and as qualified if that level was achieved with antiglaucoma medications. Preoperative and postoperative factors were evaluated for an association with postoperative success using Kaplan-Meier analysis. RESULTS: A significant reduction in mean IOP from preoperative levels was evident at the end of the follow-up. The overall surgical success rate was 57.15%. On the basis of Kaplan-Meier survival analysis, we found that patients whose IOP on the following day of the procedure was <8 mm Hg had a higher success rate than those whose 1-day postoperative IOP was higher. These patients had a percentage of success of 100%, 84.6%, and 76.9% at 1-, 3-, and 6-month postoperative follow-up, respectively. CONCLUSION: The IOP level on the first postoperative day could be considered a prognostic indicator of success in needling revision performed in failed NPDS.

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.

What did he eat?

A 13-year-old boy reported acute horizontal binocular diplopia and headache. Ten days before these symptoms he suffered from a gastrointestinal infection. Ophthalmological examination revealed bilateral ophthalmoparesis and diffuse hyporeflexia. Magnetic resonance imaging of the brain was normal. Lumbar puncture revealed albumin-cytological dissociation. There were no anti-GQ1b antibodies, but serum anti-GM1 antibodies were detected. He received intravenous immunoglobulins and had fully recovered two weeks later. Miller Fisher syndrome and its atypical variants are uncommon in childhood; nevertheless, they should be considered in the differential diagnosis of bilateral acute ophthalmoparesis.

Needling revision with marking maneuver to locate the scleral flap.

PURPOSE: To report a variation of the classical needle revision maneuver with an external marking of the scleral flap, augmented with mitomycin C (MMC) in failed non penetrating deep sclerectomy (NPDS). METHOD: This observational prospective pilot study included five consecutive patients who underwent an MMC needling revision of failed NPDS with the external marking of the scleral flap. All participants underwent a complete ophthalmologic examination and data were collected preoperatively as well as 1 day, 1 week and 1 month after the surgery. The surgical site was also evaluated during the procedure. RESULTS: A significant reduction of IOP and antiglaucomatous medication from preoperative levels was detected at the end of the follow-up period. Regarding the surgical site, we succeed in locating the scleral flap and observing the bleb formation in all cases. No significant subconjunctival bleeding was detected. CONCLUSION: This variation of the classical needling technique seems to improve intrasurgical visualization and reduces complications, which might lead to an improvement in surgical success.

Corneal Ectasia Induced by Prostaglandin Analogues.

Our purpose is to document the first case of unilateral mild corneal ectasia developed in an apparently nonpredisposed cornea after topical latanoprost treatment, and its regression after treatment withdrawal. We describe a 44-year-old man with visual impairment in his left eye (OS) and a past medical history of myopic refraction and ocular hypertension with latanoprost treatment, the rest of ocular examination was normal. A decrease in visual acuity was observed with a refractive change. Corneal tomography showed features of mild corneal ectasia in his OS. Topical prostaglandin analogue therapy was removed and replaced by other antiglaucoma topical treatment. Corneal tomography returned to normal, an improvement in the quality of vision was observed and refractive astigmatism recovered to baseline values. This case illustrates that topical latanoprost does affect the matrix metalloproteinases balance in corneal extracellular matrix, and subsequently may produce a corneal weakening. Corneal biomechanical features and corneal stiffness do probably recover after topical prostaglandin analogues withdrawal.

Miller Fisher syndrome and polyneuritis cranialis in COVID-19.

OBJECTIVE: To report 2 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented acutely with Miller Fisher syndrome and polyneuritis cranialis, respectively. METHODS: Patient data were obtained from medical records from the University Hospital "Príncipe de Asturias," Alcalá de Henares, and the University Hospital "12 de Octubre," Madrid, Spain. RESULTS: A 50-year-old man presented with anosmia, ageusia, right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia, albuminocytologic dissociation, and positive testing for anti-GD1b-immunoglobulin G antibody. Five days previously, he had developed a cough, malaise, headache, low back pain, and fever. A 39-year-old man presented with ageusia, bilateral abducens palsy, areflexia, and albuminocytologic dissociation. Three days previously, he had developed diarrhea, a low-grade fever, and poor general condition. Oropharyngeal swab test for SARS-CoV-2 by qualitative real-time reverse transcriptase PCR assay was positive in both patients and negative in the CSF. The first patient was treated with IV immunoglobulin and the second with acetaminophen. Two weeks later, both patients made a complete neurologic recovery, except for residual anosmia and ageusia in the first case. CONCLUSIONS: Our 2 cases highlight the rare occurrence of Miller Fisher syndrome and polyneuritis cranialis during the coronavirus disease 2019 (COVID-19) pandemic. These neurologic manifestations may occur because of an aberrant immune response to COVID-19. The full clinical spectrum of neurologic symptoms in patients with COVID-19 remains to be characterized.

Ideaciones suicidas en adolescentes, relaciones paternofiliales y apego a los iguales / Suicidal ideations in adolescents, paternal affiliations and attachment to peers

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Suicidal ideations in adolescents, paternal affiliations and attachment to peers. This study analyzes possible predictors variables about suicidal ideation in nonclínical teenagers, like parental socialization style (authoritarian, authoritative, indulgent and negligent) and attachment to peers. The sample is formed by 204 Spanish students from different academic centers whose age are between 12 and 18 years (M= 14.29; SD= 1.59). The results wich have been got have revealed greater suicidal ideation in teenagers with a low level of trust and communication in their relationship with their peers, as in those ones with authoritarian and negligent parents. It has not been observed differences between genus or age ranges. In agreement with the suicidal negative ideation explicative model, has been found peer alienation group, in the same form, having an authoritarian mother, establish risk factors

The nuclear corepressor 1 and the thyroid hormone receptor ß suppress breast tumor lymphangiogenesis.

Vascular Endotelial Growth Factors C and D (VEGF-C and VEGF-D) are crucial regulators of lymphangiogenesis, a main event in the metastatic spread of breast cancer tumors. Although inhibition of lymphangiogenic gene expression might be a useful therapeutic strategy to restrict the progression of cancer, the factors involved in the transcriptional repression of these genes are still unknown. We have previously shown that Nuclear Receptor Corepressor 1 (NCoR) and the thyroid hormone receptor ß1 (TRß) inhibit tumor invasion. Here we show that these molecules repress VEGF-C and VEGF-D gene transcription in breast cancer cells, reducing lymphatic vessel density and sentinel lymph node invasion in tumor xenografts. The clinical significance of these results is stressed by the finding that NCoR and TRß transcripts correlate negatively with those of the lymphangiogenic genes and the lymphatic vessel marker LYVE-1 in human breast tumors. Our results point to the use of NCoR and TRß as potential biomarkers for diagnosis or prognosis in breast cancer and suggest that further studies of these molecules as potential targets for anti-lymphangiogenic therapy are warranted.

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis.

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor ß1 (TRß) appears to be associated with cancer onset and progression. We found that expression of TRß increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRß. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.

Non-invasive detection of early retinal neuronal degeneration by ultrahigh resolution optical coherence tomography.

Optical coherence tomography (OCT) has revolutionises the diagnosis of retinal disease based on the detection of microscopic rather than subcellular changes in retinal anatomy. However, currently the technique is limited to the detection of microscopic rather than subcellular changes in retinal anatomy. However, coherence based imaging is extremely sensitive to both changes in optical contrast and cellular events at the micrometer scale, and can generate subtle changes in the spectral content of the OCT image. Here we test the hypothesis that OCT image speckle (image texture) contains information regarding otherwise unresolvable features such as organelle changes arising in the early stages of neuronal degeneration. Using ultrahigh resolution (UHR) OCT imaging at 800 nm (spectral width 140 nm) we developed a robust method of OCT image analyses, based on spatial wavelet and texture-based parameterisation of the image speckle pattern. For the first time we show that this approach allows the non-invasive detection and quantification of early apoptotic changes in neurons within 30 min of neuronal trauma sufficient to result in apoptosis. We show a positive correlation between immunofluorescent labelling of mitochondria (a potential source of changes in cellular optical contrast) with changes in the texture of the OCT images of cultured neurons. Moreover, similar changes in optical contrast were also seen in the retinal ganglion cell- inner plexiform layer in retinal explants following optic nerve transection. The optical clarity of the explants was maintained throughout in the absence of histologically detectable change. Our data suggest that UHR OCT can be used for the non-invasive quantitative assessment of neuronal health, with a particular application to the assessment of early retinal disease.

Artefact reduction for cell migration visualization using spectral domain optical coherence tomography.

Visualization of cell migration during chemotaxis using spectral domain optical coherence tomography (OCT) requires non-standard processing techniques. Stripe artefacts and camera noise floor present in OCT data prevent detailed computer-assisted reconstruction and quantification of cell locomotion. Furthermore, imaging artefacts lead to unreliable results in automated texture based cell analysis. Here we characterize three pronounced artefacts that become visible when imaging sample structures with high dynamic range, e.g. cultured cells: (i) time-varying fixed-pattern noise; (ii) stripe artefacts generated by background estimation using tomogram averaging; (iii) image modulations due to spectral shaping. We evaluate techniques to minimize the above mentioned artefacts using an 800 nm optical coherence microscope. Effect of artefact reduction is shown exemplarily on two cell cultures, i.e. Dictyostelium on nitrocellulose substrate, and retinal ganglion cells (RGC-5) cultured on a glass coverslip. Retinal imaging also profits from the proposed processing techniques.

Fast dispersion encoded full range optical coherence tomography for retinal imaging at 800 nm and 1060 nm.

The dispersion mismatch between sample and reference arm in frequency-domain optical coherence tomography (OCT) can be used to iteratively suppress complex conjugate artifacts and thereby increase the imaging range. In this paper, we propose a fast dispersion encoded full range (DEFR) algorithm that detects multiple signal components per iteration. The influence of different dispersion levels on the reconstruction quality is analyzed experimentally using a multilayered scattering phantom and in vivo retinal tomograms at 800 nm. Best results have been achieved with 30 mm SF11, with neglectable resolution decrease due to finite resolution of the spectrometer. Our fast DEFR algorithm achieves an average suppression ratio of 55 dB and typically converges within 5 to 10 iterations. The processing time on non-dedicated hardware was 5 to 10 seconds for tomograms with 512 depth scans and 4096 sampling points per depth scan. Application of DEFR to the more challenging 1060 nm wavelength region is also demonstrated by introducing an additional optical fibre in the sample arm.

Three- and four-dimensional visualization of cell migration using optical coherence tomography.

Conventionally, cell chemotaxis is studied on two-dimensional (2D) transparent surfaces, due to limitations in optical and image data-collection techniques. However, surfaces that more closely mimic the natural environment of cells are often opaque. Optical coherence tomography (OCT) is a noninvasive label-free imaging technique, which offers the potential to visualize moving cells on opaque surfaces and in three dimensions (3D). Here, we demonstrate that OCT is an effective means of time-lapse videomicroscopy of Dictyostelium cells undergoing 3D (2D+time) cell migration on nitrocellulose substrates and 4D (3D+time) chemotaxis within low-density agarose gels. The generated image sequences are compatible with current computer-based image-analysis software for quantification of cell motility. This demonstrates the utility of OCT for cell tracking and analysis of cell chemotaxis in complex environments.