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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense RNA coronavirus responsible for the COVID-19 pandemic. Since December 2019, coronavirus disease 2019 (COVID-19) has affected more than 127 million people, 2.7 million deaths globally (as per WHO dashboard, dated 31 March, 2020), the virus is capable of transmitting from human to human via inhalation of infected respiratory droplets or aerosols or contact with infected fomites. Clinically, patients with COVID-19 present with severe respiratory distress syndrome, which is very similar to the presentation of other respiratory viral infections. A huge variation in the host response exists, with the resulting symptoms varying from mild to moderate. Comorbidities such as cardiovascular disease, hypertension, diabetes, coagulation dysfunction, stroke, malignant tumor and multiple organ dysfunction syndrome, as well as age and sex, are associated with severe COVID-19 cases. So far, no targeted therapies have been developed to treat this disease and existing drugs are being investigated for repurposing. This chapter discusses the epidemiology, clinical features of COVID-19, pathogenesis and the innate and adaptive immune response mounted by the host to the SARS-CoV-2 infection. A deeper understanding of the host-pathogen interaction is fundamental to the development of a vaccine.

Eser, Sultan (Balikesir Author), Background In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. Methods CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights.Findings For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). Interpretation The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer., American Cancer Society Centers for Disease Control and Prevention Swiss Re Swiss Cancer Research foundation Swiss Cancer League Institut National du Cancer La Ligue Contre le Cancer Rossy Family Foundation US National Cancer Institute Susan G Komen Foundation

To estimate the degree to which cardiovascular risk reductions demonstrated with empagliflozin administration in the EMPA-REG OUTCOME trial might be explained by changes observed in conventional cardiovascular factors during the study.

Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia.1 These tumours characteristically present with episodes of headaches, sweating, palpitations and hypertension.1 Although rare, phaeochromocytomas are a potentially correctable cause of hypertension and delay in diagnosis can lead to increased neurological and cardiovascular morbidity and mortality.2 Surgical removal of the catecholamine-secreting tumour is the definitive therapy, and the cornerstone of pre-operative medical management is sympathetic blockade.3 Phaeochromocytomas, however, are not the only cause of elevated catecholamine levels as they could be elevated in other causes, notably physiological stress,4 antipsychotic drugs,5 anti-parkinson drugs,6 tricyclic antidepressants and cocaine use.7 The term ‘Pesudophaechromocytoma’ is used to describe these cases where a surgically amenable chromaffin tumours are not identified as the source for elevated catecholamine levels.8 In this article, we report a series of three cases with elevated catecholamines levels caused by obstructive sleep apnoea (OSA); a common medical condition which is less recognized as a cause of raised catecholamines.8 A 39-year-old man was referred to the endocrine clinic with a 2-year history of hypertension and episodic flushing. At the time of consultation, he was taking ramipril 5 mg once daily (od), atenolol 50 mg od and intra-muscular testosterone 250 mg (Sustanon 250; Organon, Cambridge, UK) every 4 weeks. He denied using any recreational drugs, anabolic steroids or antipsychotics, and had no known family history of endocrine disorders. On examination, he was uniformly obese with body mass index (BMI) of 35 kg/m2. He had generalized plethoric facies and raised blood pressure (BP) of 168/105 mmHg, but no other abnormal clinical findings. Investigations revealed elevated 24-h urinary noradrenaline levels on four occasions (Table 1). His thyroid function tests, urinary 5HIAA, dexamethasone suppression test (9 am cortisol 18 nmol/l) …

Background: There is an increased prevalence of diabetes. Doctors in training, irrespective of specialty, will have patients with diabetes under their care.\ud \ud Aim: To determine levels of confidence of doctors in training in the management of diabetes and establish their training needs in this area of clinical practice.\ud \ud Design: A national online survey of trainee doctors in the UK using a pre-validated questionnaire.\ud \ud Methods: A four-point confidence rating scale was used to rate confidence in the management of diabetes and comparators. A six-point scale was used to quantify how often trainees would contribute to the management of patients with diabetes and trainees were asked about their training in managing diabetes.\ud \ud Results: A total of 2149 doctors completed the survey. The percentage ‘fully confident’ in diagnosing diabetes was 27%, diagnosing and managing hypoglycaemia 55%, diagnosing and managing diabetic ketoacidosis 43%, managing intravenous (IV) insulin 27%, prescribing IV fluids for patients with diabetes 39% and altering diabetes therapy prior to surgery/other procedure 18%. In comparison, 66% and 65% were ‘fully confident’ in the management of angina and asthma, respectively (P 80% of the time. Respectively, 19% and 35% of respondents reported that their undergraduate and postgraduate training had prepared them adequately to optimize treatment of diabetes. The majority (>70%) wanted further training in managing all aspects of diabetes care.\ud \ud Conclusions: Trainee doctors in the UK lack confidence in the management of diabetes, are unlikely to take the initiative to optimize glycaemic control and report a need for further training.

Aims Intensive 5-day educational interventions for people with Type 1 diabetes have shown improved outcomes in a number of European studies. The aim was to assess the effectiveness of a brief (2.5 days) psycho-educational intervention.Methods Our randomized trial in a secondary-care setting had 54 and 60 participants allocated to intervention and control groups, respectively. Primary outcomes were HbA1c and severe hypoglycaemia. Secondary outcomes were blood pressure, weight, height, lipids and psychometric profile.Results HbA1c showed no statistically significant change at 3 months [difference = 0.01, 95% confidence interval (CI) –0.23, 0.26, P = 0.92], 6 months (difference = –0.06, 95% CI –0.32, 0.20, P = 0.67) and 12 months (difference = 0.01, 95% CI –0.30, 0.32, P = 0.94). Incidence of severe hypoglycaemia (per patient per year) in the intervention group (0.41) and control group (0.48) was not statistically different. Treatment satisfaction improved at 3 months (difference = 9.4, 95% CI 5.2, 13.6, P = 0.0005), 6 months (difference = 10.4, 95% CI 6.0, 14.8, P = 0.0005) and 12 months (difference = 7.1, 95% CI 2.1, 12.1, P = 0.006). The ‘Managing psychological aspects’ and ‘Setting and achieving goals’ dimensions of the Diabetes Empowerment Scale also showed significant improvement at 3, 6 and 12 months. Diabetes Knowledge Test, Illness Perception Questionnaire, Hypoglycaemia Fear Scale and Short Form 36 showed no significant change.Conclusions This brief intervention had no significant impact on HbA1c or severe hypoglycaemia, but improved diabetes treatment satisfaction and patient empowerment. Current Controlled Trials ISRCTN75807800.

Background: In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) given in addition to standard of care significantly reduced the risk of cardiovascular (CV) death by 38%, hospitalization for heart failure (HHF) by 35%, and the composite of HHF or CV death by 34% vs placebo in patients with type 2

Background. The application of gene therapy to prevent allograft rejection requires the development of noninflammatory vectors. We have therefore investigated the use of a nonviral system, transferrin-mediated lipofection, to transfer genes into the cornea with the aim of preventing corneal graft rejection. Methods. Rabbit and human corneas were cultured ex vivo and transfected with either lipofection alone or in conjunction with transferrin. The efficiency of transfection, localization, and kinetics of marker gene expression were determined. Strategies to increase gene expression, using chloroquine and EDTA, were investigated. In addition to a marker gene, a gene construct encoding viral interleukin 10 (vIL-10) was transfected and its functional effects were examined in vitro. Results. Transferrin, liposome, and DNA were demonstrated to interact with each other, forming a complex. This complex was found to deliver genes selectively to the endothelium of corneas resulting in gene expression. Treatment of corneas with chloroquine and EDTA increased the transfection efficiency eight-fold and threefold, respectively. We also demonstrated that constructs encoding vIL-10 could be delivered to the endothelium. Secreted vIL-10 was shown to be functionally active by inhibition of a mixed lymphocyte reaction. Conclusions. Our data indicate that transferrin-mediated lipofection is a comparatively efficient nonviral method for delivering genes to the corneal endothelium. Its potential for use in preventing graft rejection is shown by the ability of this system to induce vIL-10 expression at secreted levels high enough to be functional.

Following transplantation of allogeneic tissues, CD4+ recipient T cells recognize donor antigens via two distinct mechanisms: direct allorecognition, in which T cells interact with intact MHC class II on donor bone marrow-derived passenger leukocytes, and indirect allorecognition, in which T cells recognize allogeneic peptide determinants bound to self-MHC class II molecules on recipient antigen presenting cells (APCs) [1]. Activation of pro-inflammatory T cells through each of these pathways elicits different types of alloresponses leading to acute and/or chronic rejection of allografts [2]. Therefore, suppression of both of these pathways is needed to achieve transplantation tolerance. In this study, different allogeneic dendritic cells (DCs) modified to lack expression of CD80/86 or over-express indoleamine 2,3-dioxygenase (IDO) were shown to inhibit either direct and/or indirect pro-inflammatory T cell alloresponses in vitro and in vivo. Most remarkably, suppression of both pathways was achieved through linked suppression via coexpression of self- and allo-MHC molecules on semi-allogeneic DCs. Finally, this approach accomplished long-term survival of allogeneic corneal allografts whose rejection relies on indirect activation of CD4+ T cells specific for minor histocompatibility antigens. This study further demonstrates the tolerogenic potential of genetically-modified DCs that could pave the way for the design of DC-based therapy in clinical transplantation.

The endothelial cell plays a central role in the control of inflammatory processes. The recruitment of inflammatory leucocytes into the blood vessels is controlled by the expression of adhesion molecules on the endothelium as well as the secretion and presentation of chemokines. Indoleamine 2,3 dioxygenase (IDO) is an enzyme that metabolises tryptophan and is known to be central in the regulation of immune responses. IDO can be expressed on endothelial cells and can alter T-cell responses to the endothelium. We show that IDO can be readily transfected in primary endothelial cells and detail a method to determine the activity of the transfected protein.

The delivery of immunomodulatory genes into the cornea prior to transplantation is one promising strategy to improve graft survival rates. We recently reported a class of novel triblock oligopeptides that could mediate efficient gene transfer into corneal endothelial cells. Now these peptides are characterised further and it is show that they lack distinct secondary structures. Peptide complexes are also demonstrated to be weakly haemolytic and transfection efficiency is shown to be sensitive to several experimental conditions. SEM and FRET confocal images are used to study the particle morphology and to show that they condense their DNA cargo well.

Gene therapy holds a great promise to prevent allograft rejection or to induce transplant tolerance. Many achievements in vector development have allowed the progression of this therapy to become more attainable in clinical transplantation. In this articles, the authors examine the exciting development in various vector technologies that allows this form of therapy to take the central stage of clinical transplantation. Also highlighted are various therapeutic strategies that might ultimately result in the realization of gene-based treatment in clinical transplantation.

Indoleamine 2,3-dioxygenase (IDO) is an important enzyme in the regulation of immune responses; cells that express IDO can suppress T-cell responses and promote tolerance. Because of the critical role of endothelial cells in graft rejection, we have investigated the role of IDO expression by vascular endothelial cells and its consequence on immunoregulation. We compared the expression of IDO by primary human umbilical vein endothelial cells (HUVECs), human saphenous vein endothelial cells (HSVECs) and arterially derived endothelial cells using reverse transcriptase PCR, Western blotting and assays for enzymatic activity. In HUVECs IDO is upregulated by incubation with cytokines or in mycoplasma-infected cells. On the other hand HSVECs and arterially derived endothelial cells express little IDO, which is poorly upregulated upon activation (except by mycoplasma). Inhibition of IDO activity improved the ability of HUVECs to stimulate allogeneic T-cell responses. If either HUVECs or HSVECs are transfected with the gene encoding IDO, then they are incapable of stimulating allogeneic T-cell responses and induce anergy in allospecific T cells (which can also act as regulatory cells). The variable expression of IDO in different endothelial cells is important not only in understanding the role of endothelial cells in the regulation of graft rejection, but also as a potential therapeutic strategy.

Objective— Endothelium is an important target for gene therapy. We have investigated the effect of viral and nonviral vectors on the phenotype and function of endothelial cells (ECs) and developed methods to block any activation caused by these vectors. Methods and Results— Transduction of ECs with viral vectors, including adenovirus, lentiviruses, and Moloney murine leukemia virus, can induce a pro-inflammatory phenotype. This activation was reduced when nonviral vectors were used. We demonstrate that after transduction there is upregulation of dsRNA-triggered antiviral and PI3K/Akt signaling pathway. Blockade of the NFκB, PI3-K, or PKR signaling pathways all operated to inhibit partially virally induced activation, and inhibition of both PKR and PI3-K pathways totally blocked EC activation. Furthermore, inhibition of IFN-α/β in addition to PI3-K was effective at preventing EC activation. Conclusions— Viral vectors, although efficient at transducing ECs, result in their activation. Blockade of the signaling pathways involved in viral activation may be used to prevent such activation.

To examine the role of the CD28-CD80-CD86 pathway of T-lymphocyte costimulation in corneal allograft rejection and the effect of blockade of that pathway on graft survival.Kinetics of CD80 and CD86 expression in the cornea and draining lymph nodes were examined by RT-PCR and immunohistochemistry in untreated allograft recipients in a high-responder rat model. The effect of blockade of CD28-mediated costimulation was first examined by ex vivo incubation of excised Brown Norway rat donor cornea with the inhibitory protein CTLA4-Ig or an adenovirus vector (AdCTLA) expressing CTLA4-Ig, before grafting into Lewis rat recipients. A second group of graft recipients received systemic posttransplantation treatment with either CTLA4-Ig or AdCTLA.Expression of CD80 mRNA was increased in both donor and recipient cornea 16 hours after transplantation, whereas CD86 was detected constitutively, with no significant early increase. Immunohistochemistry on day 5 after transplantation demonstrated major histocompatibility complex (MHC) class II expression, no CD80, and only a trace of CD86 in corneal allografts. In lymph nodes strong MHC class II, weak CD80, and moderate CD86 expression was noted. Both donor cornea and recipient treatment with CTLA4-Ig resulted in prolonged allograft survival. AdCTLA was found to induce sustained secretion of bioactive CTLA4-Ig from corneas infected ex vivo. Survival of corneal allografts incubated with AdCTLA was marginally prolonged, and systemic treatment with AdCTLA significantly prolonged survival.Protein- or gene-based administration of CTLA4-Ig prolongs allograft survival by treatment of either the recipient or the donor tissue ex vivo before grafting.

We report a young male with sickle cell trait who developed severe hypertension and splenic infarction soon after travel to a high altitude. Hypertension persisted for three days after a diagnostic laparotomy. His blood pressure then continued to be normal over the next one and a half years. Red cell sludging in the small vessels of the kidney possibly activated the renin angiotensin system.

Background: We aimed to develop a contrast agent suitable for targeting to E-selectin expressed on activated vascular endothelium in an in vivo model of inflammation and detection by magnetic resonance (MR) imaging. Methods: Anti-murine E-selectin F(ab')2 monoclonal antibody (mAb) (MES-1) was conjugated with ultrasmall superparamagnetic iron oxide nanoparticles (USPIO). Flow cytometry, PERL staining for iron, and MR imaging were performed using CHO cells expressing mouse E-selectin (CHO-E) to detect binding of the conjugate in vitro, and a mouse model of contact hypersensitivity to oxazolone in the ear was used to investigate the in vivo characteristics of the MES-1-USPIO, with serial imaging being performed using an Oxford/Varian 9.4T MR imaging system with a custom receive-only coil. Tissue sections were stained to define the distribution of E-selectin expression and the localisation of the MES-1-USPIO conjugate. Results: The MES-1-USPIO was shown to bind to CHO-E in vitro. Following injection of MES-1-USPIO in vivo, distinct changes in the R2 relaxation rate (1/T2) characteristics could be detected in inflamed ears compared to controls. Histological analysis confirmed the vascular endothelial distribution of the MES-1-USPIO. Conclusions: E-selectin expression in vivo can be selectively and directly imaged non-invasively with magnetic resonance. This molecular imaging tool has the potential to be useful for the diagnosis and monitoring of early or occult inflammation, and may provide an attractive alternative to established clinical investigations such as the use of radiolabelled leukocytes. In addition, such an agent may have value in the investigation of some solid tumours and metastases, either by targeting tumour-associated neovasculature or tumour cells expressing E-selectin.

Many strategies for re-directing the infection spectrum of viral vectors have been described. It has been reported preformed virion-liposomes complexes, termed virosomes, are relatively stable. Virosomes were found to mediate envelope-independent transduction that allows efficient superinfection of resistant cell lines. However, the virosome-mediated transduction behaves in non-target specific manner. We developed a novel method using immunoliposomes to direct adeno (Ad)-, human deficient (HIV)-, equine anaemia virus (EIAV)- and murine Moloney leukemia (MMLV)-virosomes to vascular endothelium, which we have termed immunovirosomes. These immunovirosomes improve the transduction efficiency of the viruses and alters their tropism. We have shown improved transduction when immunovirosomes were targeted at the endocytic receptors CD71, CD62E/P and rather less good delivery when targeted at CD106. However, the enhancement of the transduction efficiency of integrating viral vectors was transient, suggesting that re-routing the entry pathway of viruses alters the expression properties of the viruses.

The microvascular endothelium (MVE) plays a major role in inflammation as well as tumour growth. Thus, the MVE represents an important therapeutic target. Peptide phage technology has been used in vivo to discover peptide sequences with binding capacity to organ specific MVE determinants in animals. The application of such powerful technology to humans has been limited by the obvious difficulties of performing phage-screening studies in vivo. By grafting human tissues into severe combined immunodeficient (SCID) mice, it is possible to target specifically human MVE determinants. Here we report for the first time the identification of synovial specific homing peptides by in vivo phage display selection in SCID mice transplanted with human synovium. Selected synovial homing peptide-phages were found to bind to human synovial graft MVE and retain their tissue homing specificity in vivo independently from phage component, disease origin of transplants and degree of human/murine graft vascularisation. In addition, the selected phages demonstrate tissue and species specificity in comparison to cotransplanted human skin grafts or mouse vasculature. Sequence analysis of the peptide inserts from synovial homing phages identified recurrent consensus motifs. One such motif maintains synovial MVE specificity both when expressed by a single phage-clone and as a free biotinylated synthetic peptide. Furthermore, the free peptide competes and inhibits, in vivo, the binding of the original peptide-phage to the cognate synovial MVE ligand. The identification of synovial homing peptides, with tissue and species specificity, may allow the construction of targeting devices capable of concentrating therapeutic/diagnostic materials to human joints.

Graphical displays are attaining greater importance in man's communication with the computers. This paper describes the characteristics and performance of an interface that has been fabricated and used to connect a plotter to a digital computer. Many computers, currently installed in India, being of the older generation, do not have graphical outputs as part of the system hardware. This paper will be of interest to those who are interested in adding graphical outputs to their existing computer system configuration at a nominal cost.

The report provides a history of the ML-419 P.E.M. program. The problems encountered, and the means of solving these problems are discussed. Thermistor materials, manufacturing processes, and production equipment are described in detail. Test data are presented for all phases of the program. A Quality Control Manual detailing pertinent inspection and quality control information is included. (Author)

Background: There is a paucity of data on the course of renal transplant in patients with immunoglobulin A (IgA) nephropathy (IgAN) from India. While the natural history of IgAN in the Indian context is rapidly progressive, the post-transplant course remains speculative. Aim: To study the graft survival in renal transplant recipients whose native kidney disease was IgAN and the incidence and correlates of recurrent disease. Settings and Designs: Retrospective case control study from a Nephrology unit of a large tertiary care center. Materials and Methods: The outcomes of 56 transplant patients (58 grafts) with biopsy-proven IgAN and of 116 patients without IgAN or diabetic nephropathy, transplanted during the same period were analyzed. Correlates of biopsy-confirmed recurrent disease were determined. Statistical Analysis: Means were analyzed by Student′s t test and Mann-Whitney test; proportions were determined by Chi-square analysis and graft survival curves were generated using the Kaplan-Meier. Results: Five-year graft survival for IgA patients was not significantly different from that in the reference group (90% and 79%, P = 0.6). During a mean follow-up of 42 months (range, 1-144), 28 event graft biopsies were required in 20 grafts of IgAN. Histological recurrence was diagnosed in five of the 20 available biopsies (25%) after a mean duration of 28 months. Recurrence did not correlate with donor status, HLA B35 and A2, recipient age, gender or immunosuppression. Conclusions: Renal transplantation is an appropriate treatment modality for IgA nephropathy patients with end-stage renal disease in India, despite the potential for recurrent disease. The posttransplant course is an indolent one when compared to the malignant pretransplant phase.

The details and operation of a slow speed card reader evolved by modifying a card verifier by the addition of suitable hardware are described. The hardware provides the option for using the same machine as a reader or verifier at a time. The possibility of converting a card punch as a reader has also been brought out.The indigenous availability of card punchers/verifiers will enable conversion of such machines at a nominal cost.