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.

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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.

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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.

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

Value of 18 FDG-PET/CT in clinical practice in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome.

PROPOS : La maladie cœliaque de l'adulte est une intolerance au gluten genetiquement determinee. Affection familiale, associee au phenotype HLA B 8 DR 3 , elle est caracterisee par une reaction lymphocytaire cytotoxique dans la muqueuse digestive, responsable de malabsorption. La maladie cœliaque de l'adulte serait une forme pauc symptomatique d'une maladie deja presente chez l'enfant. METHODE: Il s'agit d'une etude retrospective sur 19 patients chez qui le diagnostic a ete pose pour la premiere fois a l'âge adulte dans un service de Medecine Interne, sur des criteres histologiques et evolutifs. RESULTATS: Les pics de frequence d'âge au diagnostic sont de 22 ans et de 67 ans. La predominance feminine est nette. Le delai diagnostique moyen est de 3,1 ans. Les motifs d'admission ne sont pas digestifs (17/19) mais l'interrogatoire cible trouve des signes digestifs frustes. Les signes hematologiques, l'hypertransaminasemie et le desequilibre des maladies associees sont au premier plan. La principale affection associee est le diabete de type 1 (4/19). Levolution prolongee d'etats carentiels aboutit a des situations graves. CONCLUSION: La diversite clinique de la presentation de la maladie cœliaque de l'adulte doit inciter le clinicien a la suspecter sur des signes d'appel extra digestifs. La notion de pathologies associees doit l'inciter a la depister par le dosage d'anticorps specifiques devant le moindre signe carentiel. Le lymphome T digestif est la principale cause de mortalite. Le regime sans gluten est essentiel pour controler l'evolution de cette pathologie chronique.

[Adult celiac disease: importance of delay to diagnosis].

Il existe diverses methodes d’etude de la iatrogenie et/ou des effets indesirables medicamenteux en population generale. La plus utilisee de ces methodes repose sur des enquetes, le plus souvent realisees lors de l’admission des patients a l’hopital, mais egalement lors d’enquetes en ville, ces dernieres souvent sur des therapeutiques et/ou populations plus ciblees. De plus, la plupart des pays possedent un organisme de pharmacovigilance efficient, ce qui est le cas en France a travers notamment l’AFSSAPS (Agence francaise de securite sanitaire des produits de sante), pharmacovigilance chargee de recueillir les effets indesirables des medicaments apres leur mise sur le marche. Dans ce travail, nous nous proposons de faire le point sur les medicaments et classes therapeutiques a risque iatrogene a travers les donnees francaises et americaines.

Médicaments et classes thérapeutiques à risque iatrogène : études de données françaises et américaines

As people age, they become more fragile and exhibit changes in their gait and balance. This state of fragility increases their vulnerability to fall incidents. Gait and balance assessment is usually performed in a clinical setting primarily after a fall. However, daily monitoring has become essential in order to evaluate the quality of gait and alert the patient in case of a risky situation. In this context, many systems have been developed that allow the extraction of specific features in the purpose to detect or predict a fall during daily activities. Footwear systems have been of interest for being non-intrusive and adequate for everyday use. This paper describes the design and development of our proposed force-sensing shoe for gait analysis and monitoring. The system is validated by the extraction of the weight and the Center of Pressure (CoP) trajectory of 10 young volunteers. Results have shown that minor adjustment need to be performed to obtain accurate measurement of the weight. A final design with new features has been sent for manufacturing.

Design and development of a force-sensing shoe for gait analysis and monitoring

Background The clinical presentation of SARS-CoV-2 infection was initially dominated by respiratory symptoms. However, the clinical spectrum is wide and neuropsychiatric syndromes are also a source of medical concern. Our aims are to present an atypical clinical presentation of SARS-CoV-2 infection characterized by auditory hallucinations and unusual behavior and to emphasize the diversity of clinical manifestations of SARS-CoV-2 infection. Case presentation A 33-year-old woman was admitted to the emergency department (ED) with a one-day history of auditory hallucinations, unusual behavior, changes in her sleeping habits and incoherent speech. No other symptoms were reported. Blood examinations confirmed high elevated white cell count and C-reactive protein. The head CT scan was normal but the chest scan showed right ground-glass opacities in the lower zones. The oropharyngeal swab was positive for SARS-CoV-2. Based on these results, the diagnosis of SARS-CoV-2 infection was retained. The patient received no specific treatment for SARS-CoV-2 infection and only needed oxygen therapy support for 7 days. The additional dose of Olanzapine 10 mg daily was initially prescribed but the patient was back to her usual self on day 14 of hospital admission leading to its discontinuation. This clinical course was consistent with a first episode of psychosis triggered by SARS-CoV-2 infection. Conclusion Neuroinflammation owing to SARS-CoV-2 infection could be responsible for a wide and unknown spectrum of neuropsychiatric manifestations. During this pandemic, special attention should be given to patients with no previous history of psychiatric disorders presenting to ED with neuropsychiatric syndromes of unknown etiology.

Emmanuel Andrès

Papers

Value of 18 FDG-PET/CT in clinical practice in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome.

[Adult celiac disease: importance of delay to diagnosis].

Médicaments et classes thérapeutiques à risque iatrogène : études de données françaises et américaines

Design and development of a force-sensing shoe for gait analysis and monitoring

SARS-CoV-2 infection and psychiatric manifestations in a previous healthy patient