Computational single-cell RNA-seq (scRNA-seq) methods have been successfully applied to experiments representing a single condition, technology, or species to discover and define cellular phenotypes. However, identifying subpopulations of cells that are present across multiple data sets remains challenging. Here, we introduce an analytical strategy for integrating scRNA-seq data sets based on common sources of variation, enabling the identification of shared populations across data sets and downstream comparative analysis. We apply this approach, implemented in our R toolkit Seurat (http://satijalab.org/seurat/), to align scRNA-seq data sets of peripheral blood mononuclear cells under resting and stimulated conditions, hematopoietic progenitors sequenced using two profiling technologies, and pancreatic cell 'atlases' generated from human and mouse islets. In each case, we learn distinct or transitional cell states jointly across data sets, while boosting statistical power through integrated analysis. Our approach facilitates general comparisons of scRNA-seq data sets, potentially deepening our understanding of how distinct cell states respond to perturbation, disease, and evolution.

/pdf/integrating-single-cell-transcriptomic-data-across-different-3dtsi5w7ob.pdf

Integrating single-cell transcriptomic data across different conditions, technologies, and species.

The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them.

/pdf/the-host-defense-of-drosophila-melanogaster-4wk8djchw8.pdf

The Host Defense of Drosophila melanogaster

Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 [1]. The objective of these guidelines is to summarize the current evidence for treatment of different forms of aspergillosis. The quality of evidence for treatment is scored according to a standard system used in other Infectious Diseases Society of America guidelines. This document reviews guidelines for management of the 3 major forms of aspergillosis: invasive aspergillosis, chronic (and saprophytic) forms of aspergillosis, and allergic forms of aspergillosis. Given the public health importance of invasive aspergillosis, emphasis is placed on the diagnosis, treatment, and prevention of the different forms of invasive aspergillosis, including invasive pulmonary aspergillosis, sinus aspergillosis, disseminated aspergillosis, and several types of single-organ invasive aspergillosis. There are few randomized trials on the treatment of invasive aspergillosis. The largest randomized controlled trial demonstrates that voriconazole is superior to deoxycholate amphotericin B (D-AMB) as primary treatment for invasive aspergillosis. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients (A-I). Although invasive pulmonary aspergillosis accounts for the preponderance of cases treated with voriconazole, voriconazole has been used in enough cases of extrapulmonary and disseminated infection to allow one to infer that voriconazole is effective in these cases. A randomized trial comparing 2 doses of liposomal amphotericin B (L-AMB) showed similar efficacy in both arms, suggesting that liposomal therapy could be considered as alternative primary therapy in some patients (A-I). For salvage therapy, agents include lipid formulations of amphotericin (LFAB; A-II), posaconazole (B-II), itraconazole (B-II), caspofungin (B-II), or micafungin (B-II). Salvage therapy for invasive aspergillosis poses important challenges with significant gaps in knowledge. In patients whose aspergillosis is refractory to voriconazole, a paucity of data exist to guide management. Therapeutic options include a change of class using an amphotericin B (AMB) formulation or an echinocandin, such as caspofungin (B-II); further use of azoles should take into account host factors and pharmacokinetic considerations. Refractory infection may respond to a change to another drug class (B-II) or to a combination of agents (B-II). The role of combination therapy in the treatment of invasive aspergillosis as primary or salvage therapy is uncertain and warrants a prospective, controlled clinical trial. Assessment of patients with refractory aspergillosis may be difficult. In evaluating such patients, the diagnosis of invasive aspergillosis should be established if it was previously uncertain and should be confirmed if it was previously known. The drug dosage should be considered. Management options include a change to intravenous (IV) therapy, therapeutic monitoring of drug levels, change of drug class, and/or combination therapy. Antifungal prophylaxis with posaconazole can be recommended in the subgroup of HSCT recipients with graft-versus-host disease (GVHD) who are at high risk for invasive aspergillosis and in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A-I). Management of breakthrough invasive aspergillosis in the context of mould-active azole prophylaxis is not defined by clinical trial data. The approach to such patients should be individualized on the basis of clinical criteria, including host immunosuppression, underlying disease, and site of infection, as well as consideration of antifungal dosing, therapeutic monitoring of drug levels, a switch to IV therapy, and/or a switch to another drug class (B-III). Certain conditions of invasive aspergillosis warrant consideration for surgical resection of the infected focus. These include but are not limited to pulmonary lesions contiguous with the heart or great vessels, invasion of the chest wall, osteomyelitis, pericardial infection, and endocarditis (B-III). Restoration of impaired host defenses is critical for improved outcome of invasive aspergillosis (A-III). Recovery from neutropenia in a persistently neutropenic host or reduction of corticosteroids in a patient receiving high-dose glucocorticosteroids is paramount for improved outcome in invasive aspergillosis. A special consideration is made concerning recommendations for therapy of aspergillosis in uncommon sites, such as osteomyelitis and endocarditis. There are very limited data on these infections, and most involve D-AMB as primary therapy simply because of its long-standing availability. Based on the strength of the randomized study, the panel recommends voriconazole for primary treatment of these very uncommon manifestations of invasive aspergillosis (B-III). Management of the chronic or saprophytic forms of aspergillosis varies depending on the condition. Single pulmonary aspergillomas may be best managed by surgical resection (B-III), whereas chronic cavitary and chronic necrotizing pulmonary aspergillosis require long-term medical therapy (B-III). The management of allergic forms of aspergillosis involves a combination of medical and anti-inflammatory therapy. For example, management of allergic bronchopulmonary aspergillosis (ABPA) involves the administration of itraconazole and corticosteroids (A-I). © 2008 by the Infectious Diseases Society of America. All rights reserved.

/pdf/treatment-of-aspergillosis-clinical-practice-guidelines-of-22h30ces3m.pdf

Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America

Emmanuel Andres1*, Thomas Vogel2 and Pierre Olivier Lang3 1Service Medecine Interne, Diabete et Maladies metaboliques, Clinique Medicale B, Hopitaux Universitaires de Strasbourg, 67000 Strasbourg, France 2Service Medecine Interne et Geriatrie, Hopital de la Robertsau, Hopitaux Universitaires de Strasbourg, 67000 Strasbourg, France 3Service de Geriatrie et de Readaptation geriatrique, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Suisse, France *Corresponding author: Emmanuel Andres, Professor, Service de Medecine Interne, Diabete et Maladies Metaboliques, Clinique Medicale B, Hopital Civil – Hopitaux Universitaires de Strasbourg, 1 porte de l’Hopital, 67091 Strasbourg Cedex, France, Tel: (33)-(0)3-88-11-50-66; Fax: (33)-(0)3-88-11-62-62; E-mail: emmanuel.andres@chru-strasbourg.fr

Food-Cobalamin Malabsorption: A Controversial Etiology of Symptomatic Vitamin B12 Deficiency

Introduction: The mitochondrial function of circulating peripheral blood mononuclear cells (PBMCs) is an interesting new approach to cardiac diseases. Thus, PBMC’s mitochondrial respiration decreases in relation to heart failure severity. However, no data are available on heart-transplanted patients (Htx). Population and Methods: We determined PBMCs mitochondrial respiration by high-resolution respirometry (Oroboros Instruments) and superoxide anion production using electron paramagnetic resonance (Bruker-Biospin) in 20 healthy subjects and 20 matched Htx and investigated clinical, biological, echocardiographic, coronarography and biopsy characteristics. Results: PBMCs mitochondrial respiratory chain complex II respiration was decreased in Htx (4.69 ± 0.84 vs. 7.69 ± 1.00 pmol/s/million cell in controls and Htx patients, respectively; p = 0.007) and complex IV respiration was increased (24.58 ± 2.57 vs. 15.68 ± 1.67 pmol/s/million cell; p = 0.0035). Superoxide anion production was also increased in Htx (1.47 ± 0.10 vs. 1.15 ± 0.10 µmol/min; p = 0.041). The leucocyte-to-lymphocyte ratio was increased in Htx, whom complex II correlated with leucocyte number (r = 0.51, p = 0.02) and with the left ventricular posterior wall peak early diastolic myocardial velocity (r = −0.62, p = 0.005). Complex IV was increased in the two patients with acute rejection and correlated negatively with Htx’s isovolumetric relation time (r = −0.45, p = 0.045). Discussion: Although presenting with normal systolic function, Htx demonstrated abnormal PBMC’s mitochondrial respiration. Unlike immunosuppressive therapies, subclinical diastolic dysfunction might be involved in these changes. Additionally, lymphopenia might reduce complex II, and acute rejection enhances complex IV respirations. Conclusion: PBMC’s mitochondrial respiration appears modified in Htx, potentially linked to cellular shift, mild diastolic dysfunction and/or acute rejection.

/pdf/peripheral-blood-mononuclear-cells-mitochondrial-respiration-1yy7fqif.pdf

Peripheral Blood Mononuclear Cells Mitochondrial Respiration and Superoxide Anion after Heart Transplantation

Drug-induced severe neutropenia, defined as an absolute neutrophil count (NC) ≤ 0.5 x 109/L or a complete lack of neutrophils in circulating blood, is a potentially severe complication that has been related to most classes of drugs [1]. For the majority of drugs, the risk is likely to be very small. For medications such as antithyroid drugs, ticlopidine, clozapine, cotrimoxazole (trimethoprimsulfamethoxazole), sulfasalazine, methimazole, and dipyrone, the risk may be higher [2,3]. Although the pathogenesis is not yet fully clear, direct toxicity to the myeloid cell line and immune-mediated destruction are the main reported mechanisms [4].

https://www.scientificarchives.com/admin/assets/articles/pdf/tnf-alpha-inhibitors-and-neutropenia-current-state-of-art-20200707120714.pdf

TNF-alpha Inhibitors and Neutropenia: Current State of Art

Sixty-one patients were identified. One patient presented 2 episodes of IDIA (with 2 different drugs). All patients were Caucasian. The mean and median ages were 84.9 and 82 years (range, 75-95), respectively. The sex-ratio female/male was 2.4. Seventy-four percent of the patients (n=45) presented an underlying disease. Main families of causative drugs were: antibiotics (n=25, 43.8%), especially ß-lactams (n=16) and cotrimoxazole (n=9); antithyroid drugs (n=9, 15.8%); neuroleptic and anti-epileptic agents (n=7, 12.3%); and antiaggregative platelet agents (n=6, 10.5%), especially ticlopidine (n=5). There was only 1 case of self-medication. Discovery circumstances were (n=60): decrease in neutrophil blood counts (n=29, 48.3%); isolated fever (n=22, 36.7%); documented infections (n=8, 13.3%), as acute tonsillitis or pneumonia, with one case of septic shock. Clinical presentations during hospitalization were (n=58): isolated fever (fever of unknown origin) (n=16, 27.6%); documented pneumonia (n=12, 20.7%); septicemia (n=9, 15.5%); septic shock (n=5, 8.6%). The remaining symptomatic patients presented documented infections (n=14, 24.1%), as: acute pyelonephritis (n=4); sore throats and acute tonsillitis (n=4); cutaneous infections (n=1); cholecytitis (n=1); colitis (n=1); infectious spondylitis (n=1); endocarditis (n=1); and fever with deep venous thrombosis (n=1). Two patients (3.4%) remained asymptomatic during the hospitalization. During the hospitalization, 15 patients (25.9%) presented features of severe sepsis, septic shock and/or systemic inflammatory response syndrome (SIRS). Bacteriological documentation (n=54) was obtained in 23 cases (42.6%). At the time of discovery, the mean and median neutrophil counts were 1.62 and 1.5 × 109/L (range, 0.26-6.3). At nadir of the neutrophil decrease, mean and median neutrophil counts were 0.15 and 0.08 × 109/L (range, 0-0.4). Fifty-four percent of patients (n=33) had neutrophil levels of less than 0.1 × 109/L.

Emmanuel Andrès

Papers

Food-Cobalamin Malabsorption: A Controversial Etiology of Symptomatic Vitamin B12 Deficiency

Peripheral Blood Mononuclear Cells Mitochondrial Respiration and Superoxide Anion after Heart Transplantation

TNF-alpha Inhibitors and Neutropenia: Current State of Art

Idiosyncratic Agranulocytosis in Elderly Patients

Reply: Hematologic findings in food-cobalamin malabsorption related to nonimmune atrophic gastritis