‘Not finding causal effect’ is not ‘finding no causal effect’ of school closure on COVID-19

In a paper recently published in Nature Medicine, Fukumoto et al. tried to assess the government-led school closure policy during the early phase of the COVID-19 pandemic in Japan. They compared the reported incidence rates between municipalities that had and had not implemented school closure in selected periods from March–May 2020, where they rigorously matched for potential confounders, and claimed that they found no causal effect on the incidence rates of COVID-19. However, the effective sample size (ESS) of their dataset had been substantially reduced in the process of matching due to imbalanced covariates between the treatment (i.e. with closure) and control (without) municipalities, which led to the wide uncertainty in the estimates. That said, the study title "No causal effect…" is a rather strong statement because the results are also consistent with a strong mitigating effect of school closure on incidence of COVID-19.

Genetic Perturbation of CD70/CD27 Co-Stimulation Promotes the Development of Bcl6-Driven Diffuse Large B-Cell Lymphoma

Multiple co-stimulatory and co-inhibitory pathways modulate T-cell dependent anti-tumor immune responses in lymphoid malignancies. We recently defined the recurrent genetic alterations and associated substructure of diffuse large B-cell lymphoma (DLBCL), including five distinct clusters (1-5), and identified potential genetic bases for immune evasion [Nature Medicine 2018; 24:679-690]. In our series, 26% of tumors had inactivating somatic mutations or copy loss of CD70 and likely disruption of CD70/CD27 co-stimulation. CD70 and CD27 are homotrimer type II and homodimer type I transmembrane proteins and members of the TNF and TNF receptor superfamilies, respectively. CD70 is transiently expressed on certain normal B-cell and dendritic cell populations upon activation and constitutively expressed on multiple B-cell tumors. CD70 activation of CD27 + T cells promotes antigen-dependent T-cell expansion and immune surveillance of normal and malignant B cells. Patients with germline deficiencies of either CD70 or CD27 have an increased incidence of EBV-associated lymphoid malignancies, underscoring the importance of this co-stimulatory pathway. In our series, CD70 alterations were most common in Cluster 1 DLBCLs, which also exhibited recurrent BCL6 chromosomal translocations. The co-occurrence of CD70 and BCL6 genetic alterations was noteworthy because of the established role of CD8 + T-cell dependent immune surveillance in murine models of Bcl6-driven DLBCL [Nature Medicine 2014; 20:283-290]. To assess the consequences of Cd70 deficiency and perturbed CD70/CD27 co-stimulation on Bcl6-driven lymphomagenesis, we crossed the previously described Bcl6tg/+ and Cd70-/- mice to generate Cd70-/-; Bcl6tg/+ animals. In the aging cohorts, Cd70-/-; Bcl6tg/+ mice were more likely than Bcl6tg/+ animals (or the Cd70-/- or wild-type [WT] groups) to be euthanized for symptoms before the study endpoint (18 months [mo]) (5 of 18 Cd70-/-; Bcl6tg/+ euthanized for symptoms prior to the first of 9 Bcl6tg/+). Additionally, significantly greater total numbers and percentages of Cd70-/-; Bcl6tg/+ mice, in comparison to Bcl6tg/+ or Cd70-/- animals, were euthanized for symptoms (64% Cd70-/-; Bcl6tg/+ vs. 29% Bcl6tg/+, p=0.005 and 64% Cd70-/-; Bcl6tg/+ vs. 11% Cd70-/-, p=0.002). Almost all euthanized Cd70-/; Bcl6tg/+ and Bcl6tg/+ micehad massively enlarged spleens infiltrated with histopathologically confirmed DLBCLs characterized by clonal Ig gene rearrangements. Our findings indicate that genetic perturbation of Cd70 accelerates the onset and significantly increases the incidence of Bcl6-driven DLBCL. To characterize potential differences in the anti-tumor immune responses in Cd70-/-; Bcl6tg/+ and Bcl6tg/+ mice (and Cd70-/- and WT controls), we also harvested spleens from 6 animals in each of the aging cohorts at predetermined intervals (2, 6, 14 and 18 mo). We analyzed the composition of splenic-cell suspensions by flow cytometry and evaluated the intact splenic architecture and morphology with expert hematopathologists (VS, KW and SR). At 14 and 18 mo, spleens from WT and Cd70-/- animals were largely normal in appearance and size. In contrast, spleens from 14 and 18 mo Bcl6tg/+ and Cd70-/-; Bcl6tg/+ mice exhibited disordered architecture and abnormal pre-malignant lymphoid proliferation with expanded white pulp including morphologically and immunophenotypically aberrant B cells of small to large size and increased infiltrating T-cells. Additionally, significantly higher fractions of splenic CD8 + T cells from 14 and 18 mo Bcl6tg/+ and Cd70-/-; Bcl6tg/+ animals expressed the CD69 activation marker and exhibited terminal differentiation, consistent with an ongoing anti-tumor immune response. Interestingly, Bcl6tg/+ animals had significantly higher percentages of splenic TCRβ + T cells at the earlier time point (14 mo) with delayed-onset splenomegaly (at 18 mo), which is in marked contrast to the Cd70-/-; Bcl6tg/+ mice that had significantly lower percentages of splenic TCRβ + T cells at the earlier time point (14 mo) and early-onset splenomegaly (14 mo). These findings suggest that the initial T-cell mediated immune response was more effective in Bcl6tg/+ than Cd70-/-; Bcl6tg/+ animals. Taken together, our data indicate that genetic perturbation of CD70/CD27 co-stimulation limits the development of an effective anti-tumor immune response in Bcl6tg/+-driven DLBCL. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rodig: Affimed: Research Funding; Bristol-Myers-Squibb: Research Funding; Merck: Research Funding; Immunitas: Membership on an entity's Board of Directors or advisory committees; KITE/Gilead: Research Funding. Shipp: Bristol Myers Squibb: Research Funding; Immunitas Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; Merck: Research Funding; Abbvie: Other: Institution: Research Grant/Funding; Bayer: Other: Institution: Research Grant/Funding.

Thymol improves salinity tolerance of tobacco by increasing the Na+ efflux and enhancing the content of NO and GSH

Plants have evolved a lot of strategies to improve salt tolerance to cope with salt stress. Recent studies have suggested that thymol (a nature medicine) enhances the plant tolerance against abiotic stresses, but the mechanisms are rarely known. Here, we found that thymol played an important role in maintaining root growth under salt stress. Thymol rescued root growth from salt stress via ameliorating ROS (reactive oxygen species) accumulation, lipid peroxidation, and cell death. In addition, thymol enhanced the level of NO (nitric oxide) and GSH (glutathione) to repress ROS accumulation, further protecting the stability of cell membrane. Thymol-induced Na+ efflux in roots and leaves under salt stress may depend on the upregulation of SOS1, HKT1 and NHX1. Consequently, all of these evidences suggested that thymol improved tobacco salt tolerance via enhancing NO and GSH content as well as inducing Na+ efflux.

Importation Risk Stratification for COVID19 using Quantitative Serology

Recent work (Khoury et al.,Nature Medicine2021, 27 (7), 1205-1211) has shown that measurement of IgG antibody concentration in blood correlates well with vaccine efficacy. The present communication builds on this work and considers the probability of infection given immunity, taking into account the distribution across the population of antibody concentration in vaccinated or convalescent people. The model is consistent with the observed rates of breakthrough infection following vaccination or previous infection. The model is then developed to consider the use of quantitative measurement of antibody concentration on arrival as an aid to risk stratification of travellers. The model indicates that such a measurement could significantly decrease the quarantine time required to achieve a given level of importation risk.

Artificial Intelligence Is Reshaping Healthcare Amid Covid-19: A Review in the Context of Diagnosis & Prognosis

Preventing respiratory failure is crucial in a large proportion of COVID-19 patients infected with SARS-CoV-2 virus pneumonia termed as Novel Coronavirus Pneumonia (NCP). Rapid diagnosis and detection of high-risk patients for effective interventions have been shown to be troublesome. Using a large, computed tomography (CT) database, we developed an artificial intelligence (AI) parameter to diagnose NCP and distinguish it from other kinds of pneumonia and traditional controls. The literature was studied and analyzed from diverse assets which include Scopus, Nature medicine, IEEE, Google scholar, Wiley Library, and PubMed. The search terms used were ‘Covid-19’, ‘AI’, ‘diagnosis’, and ‘prognosis’. To strengthen the overall performance of AI in COVID-19 diagnosis and prognosis, we segregated several components to perceive threats and opportunities, as well as their inter-dependencies that affect the healthcare sector. This paper seeks to pick out the crucial fulfillment of factors for AI with inside the healthcare sector in the Indian context. Using critical literature review and experts’ opinion, a total of 11 factors affecting COVID-19 diagnosis and prognosis were detected, and we eventually used an interpretive structural model (ISM) to build a framework of interrelationships among the identified factors. Finally, the matrice d’impacts croisés multiplication appliquée á un classment (MICMAC) analysis resulted the driving and dependence powers of these identified factors. Our analysis will help healthcare stakeholders to realize the requirements for successful implementation of AI.

Thymol improves salinity tolerance of tobacco by increasing the Na + efflux and enhancing the content of NO and GSH

Plants have evolved a lot of strategies to improve salt tolerance to cope with salt stress. Recent studies have suggested that thymol (a nature medicine) enhances the plant tolerance against abiotic stresses, but the mechanisms are rarely known. Here, we found that thymol played an important role in maintaining root growth under salt stress. Thymol rescued root growth from salt stress via ameliorating ROS (reactive oxygen species) accumulation, lipid peroxidation, and cell death. In addition, thymol enhanced the level of NO (nitric oxide) and GSH (glutathione) to repress ROS accumulation, further protecting the stability of cell membrane. Thymol-induced Na+ efflux in roots and leaves under salt stress may depend on the upregulation of SOS1, HKT1 and NHX1. Consequently, all of these evidences suggested that thymol improved tobacco salt tolerance via enhancing NO and GSH content as well as inducing Na+ efflux.

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593–596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251–262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

Identifizierung von Diabetes-Risikogruppen eröffnet Chancen für frühzeitige Therapie

Um noch nicht erkrankte Personen mit einem hohen Erkrankungsrisiko für Typ-2-Diabetes frühzeitig identifizieren zu können, hat Prof. Dr. med. Robert Wagner, Tübingen, entsprechende Risikogruppen festgelegt. Für seine Erkenntnisse, die im renommierten Fachblatt „Nature Medicine“ publiziert wurden, erhielt er im Rahmen des Internistenkongresses den Präventionspreis 2021.

A importância da implantação de medidas de prevenção das infecções sexualmente transmissíveis em mulheres idosas

Introdução: Com a mudança da pirâmide etária brasileira e o aumento da expectativa de vida, assuntos referentes à saúde da pessoa idosa ganham maior destaque e necessidade de serem abordados por seu impacto na Saúde Pública. Estudos epidemiológicos demonstram aumento nas taxas de infecções sexualmente transmissíveis (IST) em pessoas acima dos 50 anos na América do Norte. No Brasil não existem dados com amplitude nacional sobre o assunto, porém observa-se aumento significativo dessas taxas em estudos locais, particularmente das taxas de prevalência do vírus da imunodeficiência humana (HIV) em mulheres acima dos 60 anos de idade. Objetivo: Analisar a importância da implantação de medidas de prevenção das infecções sexualmente transmissíveis em mulheres idosas. Métodos: Artigo de revisão bibliográfica realizada por meio de um levantamento na literatura utilizando as plataformas: PubMed, Nature, Science, Word Health Organization, The New England Journal of Medicine, Nature medicine. As palavras-chave utilizadas foram: infecções sexualmente transmissíveis, pessoa idosa e mulheres. Foram incluídos artigos nacionais e internacionais publicados no período de 2017 a 2021, cujo título e conteúdo se adequaram à temática estudada. Foram excluídos os artigos que não correspondiam à temática abordada, teses, monografias, dissertações, livros ou artigos que não tratavam da temática de forma satisfatória. Resultados: Os dados referentes às IST em mulheres idosas no Brasil são escassos, mas achados locais de incidência aumentada de HIV em mulheres acima de 60 anos são extremamente relevantes para o estudo em questão. Foram encontrados diversos elementos relacionados ao aumento das taxas de IST em idosas, entre os quais merecem destaque a falta de conhecimento sobre as formas de transmissão e prevenção das IST e a dificuldade de reconhecimento das idosas como sexualmente ativas pela sociedade e pelos profissionais de saúde, bem como o próprio contexto sexual mais rígido que foi imposto a essas pacientes. Alguns estudos atribuíram a inexistência de medidas de prevenção específicas como determinantes no aumento das taxas de transmissão de IST em mulheres idosas. Conclusão: Este estudo teve como objetivo analisar a importância da implantação de medidas de prevenção de IST em mulheres idosas. Diante da condição epidemiológica de aumento das IST nesse grupo e de os elementos relacionados a esse aumento estarem intimamente ligados a vulnerabilidades dessas pacientes, medidas de prevenção específicas para esse grupo etário fazem-se necessárias para propiciar um envelhecimento saudável com sexualidade ativa e segura. Em virtude da escassez de dados amplos sobre a problemática, mais estudos são necessários para aprofundar os conhecimentos sobre o assunto e propiciar medidas de combate, diagnóstico e tratamento das IST em mulheres idosas.

Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Colorectal cancer (CRC) worldwide affects over a quarter of a million people each year. Most sporadic CRCs develop through formation of polypoid adenomas and are preceded by intramucosal carcinoma (Stage 0), which can progress into malignant forms. Detection of early cancers and their endoscopic removal are priorities for cancer control. Human gut microbiome has been associated to CRC development, and its comprehensive characterization is of a great importance to assess its potential as a diagnostic marker. We performed whole shotgun metagenomic sequencing and CE-TOFMS-based metabolomic studies on fecal samples collected from 616 participants undergoing colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. As a result, microbiome and metabolite shifts were apparent in cases of multiple polypoid adenomas (MP) and Stage 0, in addition to more advanced lesions (Stage I/II and Stage III/IV). Two distinct patterns of microbiome elevations were found (P<0.005). First, CRC-associated species including Fusobacterium nucleatum were elevated continuously from Stage 0 to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in Stage 0, were elevated only in MP and/or in Stage 0. Metabolome analyses showed elevation of branched-chain amino acids and phenylalanine in Stage 0 and bile acids including deoxycholate in MP and/or Stage 0. Metagenomic functional analyses showed amino acid metabolism and sulfide producing pathways were associated with CRCs. Our study indicates possible etiological and diagnostic significance of fecal microbiota and metabolite in the very early stages of CRC (Yachida et al., Nature Medicine 2019).