Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

MEDICAL LITERATURE has been deluged during the past few years with books and papers on penicillin; but a book which has been produced under the general editorship of Sir Alexander Fleming himself represents a complete and authoritative summary of penicillin therapy as it stands today.' The book contains a series of independent contributions by \"experienced and eminent men who have worked with penicillin in Great Britain\". Their opinions and practical methods differ slightly, and there is some overlapping; but these are not disadvantageous, comparison and contrast lending interest to the reading. In the first or general section of the book Fleming contributes two chapters, one on the history and development of penicillin, introducing some interesting sidelights in the romance of discovery, the other on the bacteriological control of penicillin therapy. In both chapters the information is set out in meticulous detail and with a clarity and simplicity which can be enjoyed by all readers. Fleming also gives the right perspective to the place of penicillin amongst the antibiotics and lays down the principles of treatment. Both chapters are well illustrated and are the most outstanding in the book. Included in this first section also are chapters on the chemistry and manufacture of penicillin and its pharmacy, pharmacology and methods of administration. The second section of the book is entirely clinical, giving each author's view on the use of penicillin therapy in a disease or an infection of some particular region of the body. The entire range of peniCillin-sensitive conditions is considered in twenty authoritative and clearly written chapters; these contain many references and illustrations. Dental and veterinary diseases are also given fairly full consideration. The final section is a condensed resume of much of the preceding chapters and is written for. the general practttioner. This chapter is superttuous: it does not contain enough detall to be of much practical value. The book as a Whole, however, will undoubtedly be considered a classical contribution to medical literature and is strongly recommended, not only because of the general interest of its topic, but as a reference book on penicillin therapy of hitherto unequalled excellence. The typography, although conforming to war economy standards, is clear and the paper is good. There is an excellent list of references and the index is satisfactory.

Gray's Anatomy

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.

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A dynamic COVID-19 immune signature includes associations with poor prognosis.

Epidemiological studies have indicated that susceptibility of human adults to hypertension and cardiovascular disease may result from intrauterine growth restriction and low birth weight induced by maternal undernutrition. Although the 'foetal origins of adult disease' hypothesis has significant relevance to preventative healthcare, the origin and biological mechanisms of foetal programming are largely unknown. Here, we investigate the origin, embryonic phenotype and potential maternal mechanisms of programming within an established rat model. Maternal low protein diet (LPD) fed during only the preimplantation period of development (0-4.25 days after mating), before return to control diet for the remainder of gestation, induced programming of altered birthweight, postnatal growth rate, hypertension and organ/body-weight ratios in either male or female offspring at up to 12 weeks of age. Preimplantation embryos collected from dams after 0-4.25 days of maternal LPD displayed significantly reduced cell numbers, first within the inner cell mass (ICM; early blastocyst), and later within both ICM and trophectoderm lineages (mid/late blastocyst), apparently induced by a slower rate of cellular proliferation rather than by increased apoptosis. The LPD regimen significantly reduced insulin and essential amino acid levels, and increased glucose levels within maternal serum by day 4 of development. Our data indicate that long-term programming of postnatal growth and physiology can be induced irreversibly during the preimplantation period of development by maternal protein undernutrition. Further, we propose that the mildly hyperglycaemic and amino acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of 'metabolic stress', restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages.

Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon) BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)) The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 82–182× that of a panel of SARS-CoV-2-convalescent human sera The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728) BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge

/pdf/bnt162b-vaccines-protect-rhesus-macaques-from-sars-cov-2-2qh37gbx2p.pdf

BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

The embryonic origin of endocrine cells of the gastrointestinal tract.

Anatomy has served as a cornerstone in the training of various allied and clinical disciplines and has traditionally been based on dissection of the human body. Thus, to pursue this method of teaching and learning, access to cadavers is of continuing importance. Over a significant period of time unclaimed cadavers have performed an essential role in the teaching of anatomy in South Africa and in Africa. As recent cadaver numbers were declining at the School of Anatomical Sciences, University of the Witwatersrand, Johannesburg and difficulty in procurement was being experienced, the purpose of this study was to critically evaluate the composition of our cadaver population over time so as to provide possible strategies to arrest the decline. A retrospective, quantitative analysis of cadaver records from the School of Anatomical Sciences between 1921 and 2013 was undertaken. Analysis included a comparison of Poisson counts and Fischer's exact test. A significant decrease in the number of cadavers received during the period 2000–2013 and a slow bequest program over the same period of time has led to concerns about the sustainability of teaching anatomy through dissection. Decreases in the numbers of males and cadavers of the black population group occurred between 1990 and 2013, and of bequests from 2000 to 2013. An influence on the cadaver population from a changing political climate and change in socioeconomic status of part of the population was perceived. Changes in sex and population group of the cadavers may have a long-term effect on teaching and research. Anat Sci Educ. © 2014 American Association of Anatomists.

Transformation of a cadaver population: Analysis of a South African cadaver program, 1921–2013

Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives.

The pancreas of the naked mole-rat (Heterocephalus glaber): an ultrastructural and immunocytochemical study of the endocrine component of thermoneutral and cold acclimated animals.

The serum levels of oestrogen and progesterone in hyperstimulated, pregnant rats were compared with those of normal pregnant animals. The endometrial morphology was studied before (4.5 days), at the time of (5.5 days) and after (6.5 days) implantation. In the hyperstimulated group serum oestradiol levels were significantly higher than in the controls at 2.5 and 4.5 days, while progesterone levels were similar in the two groups. Consequently the progesterone:oestradiol ratio was significantly lower in the experimental groups prior to implantation. Significant changes in the endometrium caused by the raised oestradiol levels, included an early increase in gland epithelial height, increased surface epithelial height, increased number and length of microvilli, deficiencies in the glycocalyx and decreased mitotic activity in the surface epithelium and stromal cells. In addition, epithelial cell degeneration and failure of decidualisation of stromal cells was observed. These morphological changes adversely affect embryo attachment and implantation. Similar pathological changes in the endometrium may occur in human in vitro fertilisation utilising superovulation and may be an important factor in the low success rate of these programmes.

Exogenous gonadotropins--serum oestrogen and progesterone and the effect on endometrial morphology in the rat.

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