Progressive outer retinal necrosis in a renal transplant recipient: a rare treatment success

Renal transplant recipients (RTRs) are subject to a variety of opportunistic infections. We present a rare case of varicella zoster virus-derived progressive outer retinal necrosis in an RTR, who presented with painless visual blurring. This clinical entity heralds an extremely poor visual prognosis and is an important condition to consider in any immunocompromised host. Early diagnosis by aqueous fluid sampling and immediate institution of combined systemic and intravitreal antiviral therapy was successful in this individual.postprin

A λ-lemma for Normally Hyperbolic Invariant Manifolds

a

The cytochrome bd-I respiratory oxidase augments survival of multidrug-resistant Escherichia coli during infection

Nitric oxide (NO) is a toxic free radical produced by neutrophils and macrophages in response to infection. Uropathogenic Escherichia coli (UPEC) induces a variety of defence mechanisms in response to NO, including direct NO detoxification (Hmp, NorVW, NrfA), iron-sulphur cluster repair (YtfE), and the expression of the NO-tolerant cytochrome bd-I respiratory oxidase (CydAB). The current study quantifies the relative contribution of these systems to UPEC growth and survival during infection. Loss of the flavohemoglobin Hmp and cytochrome bd-I elicit the greatest sensitivity to NO-mediated growth inhibition, whereas all but the periplasmic nitrite reductase NrfA provide protection against neutrophil killing and promote survival within activated macrophages. Intriguingly, the cytochrome bd-I respiratory oxidase was the only system that augmented UPEC survival in a mouse model after 2 days, suggesting that maintaining aerobic respiration under conditions of nitrosative stress is a key factor for host colonisation. These findings suggest that while UPEC have acquired a host of specialized mechanisms to evade nitrosative stresses, the cytochrome bd-I respiratory oxidase is the main contributor to NO tolerance and host colonisation under microaerobic conditions. This respiratory complex is therefore of major importance for the accumulation of high bacterial loads during infection of the urinary tract

Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

BACKGROUND: Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. METHODS: Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. RESULTS: Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. CONCLUSION: Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors

SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme

INTRODUCTION: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population

Management of retinal vascular diseases: a patient-centric approach

Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases

Mapping inequalities in exclusive breastfeeding in low- and middle-income countries, 2000–2018

Exclusive breastfeeding (EBF)-giving infants only breast-milk for the first 6 months of life-is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for example, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization's Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030.This work was primarily supported by grant no. OPP1132415 from the Bill & Melinda Gates Foundation. Co-authors used by the Bill & Melinda Gates Foundation (E.G.P. and R.R.3) provided feedback on initial maps and drafts of this manuscript. L.G.A. has received support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Código de Financiamento 001 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant nos. 404710/2018-2 and 310797/2019-5). O.O.Adetokunboh acknowledges the National Research Foundation, Department of Science and Innovation and South African Centre for Epidemiological Modelling and Analysis. M.Ausloos, A.Pana and C.H. are partially supported by a grant from the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project no. PN-III-P4-ID-PCCF-2016-0084. P.C.B. would like to acknowledge the support of F. Alam and A. Hussain. T.W.B. was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. K.Deribe is supported by the Wellcome Trust (grant no. 201900/Z/16/Z) as part of his international intermediate fellowship. C.H. and A.Pana are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project no. PN-III-P2-2.1-SOL-2020-2-0351. B.Hwang is partially supported by China Medical University (CMU109-MF-63), Taichung, Taiwan. M.Khan acknowledges Jatiya Kabi Kazi Nazrul Islam University for their support. A.M.K. acknowledges the other collaborators and the corresponding author. Y.K. was supported by the Research Management Centre, Xiamen University Malaysia (grant no. XMUMRF/2020-C6/ITM/0004). K.Krishan is supported by a DST PURSE grant and UGC Centre of Advanced Study (CAS II) awarded to the Department of Anthropology, Panjab University, Chandigarh, India. M.Kumar would like to acknowledge FIC/NIH K43 TW010716-03. I.L. is a member of the Sistema Nacional de Investigación (SNI), which is supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT), Panamá. M.L. was supported by China Medical University, Taiwan (CMU109-N-22 and CMU109-MF-118). W.M. is currently a programme analyst in Population and Development at the United Nations Population Fund (UNFPA) Country Office in Peru, which does not necessarily endorses this study. D.E.N. acknowledges Cochrane South Africa, South African Medical Research Council. G.C.P. is supported by an NHMRC research fellowship. P.Rathi acknowledges support from Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India. Ramu Rawat acknowledges the support of the GBD Secretariat for supporting the reviewing and collaboration of this paper. B.R. acknowledges support from Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal. A.Ribeiro was supported by National Funds through FCT, under the programme of ‘Stimulus of Scientific Employment—Individual Support’ within the contract no. info:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND/02386/2018/CP1538/CT0001/PT. S.Sajadi acknowledges colleagues at Global Burden of Diseases and Local Burden of Disease. A.M.S. acknowledges the support from the Egyptian Fulbright Mission Program. F.S. was supported by the Shenzhen Science and Technology Program (grant no. KQTD20190929172835662). A.Sheikh is supported by Health Data Research UK. B.K.S. acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for all the academic support. B.U. acknowledges support from Manipal Academy of Higher Education, Manipal. C.S.W. is supported by the South African Medical Research Council. Y.Z. was supported by Science and Technology Research Project of Hubei Provincial Department of Education (grant no. Q20201104) and Outstanding Young and Middle-aged Technology Innovation Team Project of Hubei Provincial Department of Education (grant no. T2020003). The funders of the study had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. All maps presented in this study are generated by the authors and no permissions are required to publish them

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe