Journal: Nat Med

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Abstract

Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.

Asnicar F, Berry SE, Valdes AM, Nguyen LH, ... Spector TD, Segata N

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.



Nat Med: 10 Jan 2021; epub ahead of print
Asnicar F, Berry SE, Valdes AM, Nguyen LH, ... Spector TD, Segata N
Nat Med: 10 Jan 2021; epub ahead of print | PMID: 33432175
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Abstract

The distribution of cellular turnover in the human body.

Sender R, Milo R

We integrated ubiquity, mass and lifespan of all major cell types to achieve a comprehensive quantitative description of cellular turnover. We found a total cellular mass turnover of 80 ± 20 grams per day, dominated by blood cells and gut epithelial cells. In terms of cell numbers, close to 90% of the (0.33 ± 0.02) × 10 cells per day turnover was blood cells.



Nat Med: 10 Jan 2021; epub ahead of print
Sender R, Milo R
Nat Med: 10 Jan 2021; epub ahead of print | PMID: 33432173
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Abstract

Robust breast cancer detection in mammography and digital breast tomosynthesis using an annotation-efficient deep learning approach.

Lotter W, Diab AR, Haslam B, Kim JG, ... Vijayaraghavan GR, Gregory Sorensen A

Breast cancer remains a global challenge, causing over 600,000 deaths in 2018 (ref. ). To achieve earlier cancer detection, health organizations worldwide recommend screening mammography, which is estimated to decrease breast cancer mortality by 20-40% (refs. ). Despite the clear value of screening mammography, significant false positive and false negative rates along with non-uniformities in expert reader availability leave opportunities for improving quality and access. To address these limitations, there has been much recent interest in applying deep learning to mammography, and these efforts have highlighted two key difficulties: obtaining large amounts of annotated training data and ensuring generalization across populations, acquisition equipment and modalities. Here we present an annotation-efficient deep learning approach that (1) achieves state-of-the-art performance in mammogram classification, (2) successfully extends to digital breast tomosynthesis (DBT; \'3D mammography\'), (3) detects cancers in clinically negative prior mammograms of patients with cancer, (4) generalizes well to a population with low screening rates and (5) outperforms five out of five full-time breast-imaging specialists with an average increase in sensitivity of 14%. By creating new \'maximum suspicion projection\' (MSP) images from DBT data, our progressively trained, multiple-instance learning approach effectively trains on DBT exams using only breast-level labels while maintaining localization-based interpretability. Altogether, our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide.



Nat Med: 10 Jan 2021; epub ahead of print
Lotter W, Diab AR, Haslam B, Kim JG, ... Vijayaraghavan GR, Gregory Sorensen A
Nat Med: 10 Jan 2021; epub ahead of print | PMID: 33432172
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Abstract

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

Park J, Lucas AM, Zhang X, Chaudhary K, ... Ritchie MD, Rader DJ

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into \'gene burdens\' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.



Nat Med: 10 Jan 2021; epub ahead of print
Park J, Lucas AM, Zhang X, Chaudhary K, ... Ritchie MD, Rader DJ
Nat Med: 10 Jan 2021; epub ahead of print | PMID: 33432171
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Abstract

Modeling human adaptive immune responses with tonsil organoids.

Wagar LE, Salahudeen A, Constantz CM, Wendel BS, ... Kuo CJ, Davis MM

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.



Nat Med: 10 Jan 2021; epub ahead of print
Wagar LE, Salahudeen A, Constantz CM, Wendel BS, ... Kuo CJ, Davis MM
Nat Med: 10 Jan 2021; epub ahead of print | PMID: 33432170
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Abstract

Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes.

Wagner R, Heni M, Tabák AG, Machann J, ... Häring HU, Fritsche A

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.



Nat Med: 03 Jan 2021; epub ahead of print
Wagner R, Heni M, Tabák AG, Machann J, ... Häring HU, Fritsche A
Nat Med: 03 Jan 2021; epub ahead of print | PMID: 33398163
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Abstract

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.

Yu J, Green MD, Li S, Sun Y, ... Alva A, Zou W

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8 T cells from systemic circulation. Within the liver, activated antigen-specific FasCD8 T cells undergo apoptosis following their interaction with FasLCD11bF4/80 monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8 T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.



Nat Med: 03 Jan 2021; epub ahead of print
Yu J, Green MD, Li S, Sun Y, ... Alva A, Zou W
Nat Med: 03 Jan 2021; epub ahead of print | PMID: 33398162
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Abstract

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Wang R, Dang M, Harada K, Han G, ... Ajani JA, Wang L

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.



Nat Med: 03 Jan 2021; epub ahead of print
Wang R, Dang M, Harada K, Han G, ... Ajani JA, Wang L
Nat Med: 03 Jan 2021; epub ahead of print | PMID: 33398161
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Abstract

Brown adipose tissue is associated with cardiometabolic health.

Becher T, Palanisamy S, Kramer DJ, Eljalby M, ... Mark A, Cohen P

White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear. Here we retrospectively categorized 134,529 F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.



Nat Med: 03 Jan 2021; epub ahead of print
Becher T, Palanisamy S, Kramer DJ, Eljalby M, ... Mark A, Cohen P
Nat Med: 03 Jan 2021; epub ahead of print | PMID: 33398160
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Abstract

A neuroimaging biomarker for sustained experimental and clinical pain.

Lee JJ, Kim HJ, Čeko M, Park BY, ... Wager TD, Woo CW

Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation.



Nat Med: 03 Jan 2021; epub ahead of print
Lee JJ, Kim HJ, Čeko M, Park BY, ... Wager TD, Woo CW
Nat Med: 03 Jan 2021; epub ahead of print | PMID: 33398159
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Abstract

Immune determinants of COVID-19 disease presentation and severity.

Brodin P

COVID-19, caused by SARS-CoV-2 infection, is mild to moderate in the majority of previously healthy individuals, but can cause life-threatening disease or persistent debilitating symptoms in some cases. The most important determinant of disease severity is age, with individuals over 65 years having the greatest risk of requiring intensive care, and men are more susceptible than women. In contrast to other respiratory viral infections, young children seem to be less severely affected. It is now clear that mild to severe acute infection is not the only outcome of COVID-19, and long-lasting symptoms are also possible. In contrast to severe acute COVID-19, such \'long COVID\' is seemingly more likely in women than in men. Also, postinfectious hyperinflammatory disease has been described as an additional outcome after SARS-CoV-2 infection. Here I discuss our current understanding of the immunological determinants of COVID-19 disease presentation and severity and relate this to known immune-system differences between young and old people and between men and women, and other factors associated with different disease presentations and severity.



Nat Med: 30 Dec 2020; 27:28-33
Brodin P
Nat Med: 30 Dec 2020; 27:28-33 | PMID: 33442016
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Abstract

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, ... Blakeley JO, Clapp DW

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.



Nat Med: 30 Dec 2020; 27:165-173
Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, ... Blakeley JO, Clapp DW
Nat Med: 30 Dec 2020; 27:165-173 | PMID: 33442015
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Abstract

An algorithmic approach to reducing unexplained pain disparities in underserved populations.

Pierson E, Cutler DM, Leskovec J, Mullainathan S, Obermeyer Z

Underserved populations experience higher levels of pain. These disparities persist even after controlling for the objective severity of diseases like osteoarthritis, as graded by human physicians using medical images, raising the possibility that underserved patients\' pain stems from factors external to the knee, such as stress. Here we use a deep learning approach to measure the severity of osteoarthritis, by using knee X-rays to predict patients\' experienced pain. We show that this approach dramatically reduces unexplained racial disparities in pain. Relative to standard measures of severity graded by radiologists, which accounted for only 9% (95% confidence interval (CI), 3-16%) of racial disparities in pain, algorithmic predictions accounted for 43% of disparities, or 4.7× more (95% CI, 3.2-11.8×), with similar results for lower-income and less-educated patients. This suggests that much of underserved patients\' pain stems from factors within the knee not reflected in standard radiographic measures of severity. We show that the algorithm\'s ability to reduce unexplained disparities is rooted in the racial and socioeconomic diversity of the training set. Because algorithmic severity measures better capture underserved patients\' pain, and severity measures influence treatment decisions, algorithmic predictions could potentially redress disparities in access to treatments like arthroplasty.



Nat Med: 30 Dec 2020; 27:136-140
Pierson E, Cutler DM, Leskovec J, Mullainathan S, Obermeyer Z
Nat Med: 30 Dec 2020; 27:136-140 | PMID: 33442014
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Abstract

Targeting metastatic cancer.

Ganesh K, Massagué J

Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.



Nat Med: 30 Dec 2020; 27:34-44
Ganesh K, Massagué J
Nat Med: 30 Dec 2020; 27:34-44 | PMID: 33442008
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Abstract

T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.

Ewer KJ, Barrett JR, Belij-Rammerstorfer S, Sharpe H, ... Lambe T,

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses and might reduce the potential for disease enhancement. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. ). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838) given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4 T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8 T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.



Nat Med: 16 Dec 2020; epub ahead of print
Ewer KJ, Barrett JR, Belij-Rammerstorfer S, Sharpe H, ... Lambe T,
Nat Med: 16 Dec 2020; epub ahead of print | PMID: 33335323
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Abstract

Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.

Barrett JR, Belij-Rammerstorfer S, Dold C, Ewer KJ, ... Pollard AJ,

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.



Nat Med: 16 Dec 2020; epub ahead of print
Barrett JR, Belij-Rammerstorfer S, Dold C, Ewer KJ, ... Pollard AJ,
Nat Med: 16 Dec 2020; epub ahead of print | PMID: 33335322
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Abstract

Individual and community-level risk for COVID-19 mortality in the United States.

Jin J, Agarwala N, Kundu P, Harvey B, ... Wallace E, Chatterjee N

Reducing COVID-19 burden for populations will require equitable and effective risk-based allocations of scarce preventive resources, including vaccinations. To aid in this effort, we developed a general population risk calculator for COVID-19 mortality based on various sociodemographic factors and pre-existing conditions for the US population, combining information from the UK-based OpenSAFELY study with mortality rates by age and ethnicity across US states. We tailored the tool to produce absolute risk estimates in future time frames by incorporating information on pandemic dynamics at the community level. We applied the model to data on risk factor distribution from a variety of sources to project risk for the general adult population across 477 US cities and for the Medicare population aged 65 years and older across 3,113 US counties, respectively. Validation analyses using 54,444 deaths from 7 June to 1 October 2020 show that the model is well calibrated for the US population. Projections show that the model can identify relatively small fractions of the population (for example 4.3%) that might experience a disproportionately large number of deaths (for example 48.7%), but there is wide variation in risk across communities. We provide a web-based risk calculator and interactive maps for viewing community-level risks.



Nat Med: 10 Dec 2020; epub ahead of print
Jin J, Agarwala N, Kundu P, Harvey B, ... Wallace E, Chatterjee N
Nat Med: 10 Dec 2020; epub ahead of print | PMID: 33311702
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Abstract

A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial.

Nachbagauer R, Feser J, Naficy A, Bernstein DI, ... Palese P, Krammer F

Seasonal influenza viruses constantly change through antigenic drift and the emergence of pandemic influenza viruses through antigenic shift is unpredictable. Conventional influenza virus vaccines induce strain-specific neutralizing antibodies against the variable immunodominant globular head domain of the viral hemagglutinin protein. This necessitates frequent re-formulation of vaccines and handicaps pandemic preparedness. In this completed, observer-blind, randomized, placebo-controlled phase I trial (NCT03300050), safety and immunogenicity of chimeric hemagglutinin-based vaccines were tested in healthy, 18-39-year-old US adults. The study aimed to test the safety and ability of the vaccines to elicit broadly cross-reactive antibodies against the hemagglutinin stalk domain. Participants were enrolled into five groups to receive vaccinations with live-attenuated followed by AS03-adjuvanted inactivated vaccine (n = 20), live-attenuated followed by inactivated vaccine (n = 15), twice AS03-adjuvanted inactivated vaccine (n = 16) or placebo (n = 5, intranasal followed by intramuscular; n = 10, twice intramuscular) 3 months apart. Vaccination was found to be safe and induced a broad, strong, durable and functional immune response targeting the conserved, immunosubdominant stalk of the hemagglutinin. The results suggest that chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.



Nat Med: 06 Dec 2020; epub ahead of print
Nachbagauer R, Feser J, Naficy A, Bernstein DI, ... Palese P, Krammer F
Nat Med: 06 Dec 2020; epub ahead of print | PMID: 33288923
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Abstract

Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.

Khan TA, Revah O, Gordon A, Yoon SJ, ... Dolmetsch RE, Paşca SP

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.



Nat Med: 29 Nov 2020; 26:1888-1898
Khan TA, Revah O, Gordon A, Yoon SJ, ... Dolmetsch RE, Paşca SP
Nat Med: 29 Nov 2020; 26:1888-1898 | PMID: 32989314
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Abstract

Global maps of travel time to healthcare facilities.

Weiss DJ, Nelson A, Vargas-Ruiz CA, Gligorić K, ... Bhatt S, Gething PW

Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.



Nat Med: 29 Nov 2020; 26:1835-1838
Weiss DJ, Nelson A, Vargas-Ruiz CA, Gligorić K, ... Bhatt S, Gething PW
Nat Med: 29 Nov 2020; 26:1835-1838 | PMID: 32989313
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Abstract

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Nakamura Y, Taniguchi H, Ikeda M, Bando H, ... Odegaard JI, Yoshino T

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.



Nat Med: 29 Nov 2020; 26:1859-1864
Nakamura Y, Taniguchi H, Ikeda M, Bando H, ... Odegaard JI, Yoshino T
Nat Med: 29 Nov 2020; 26:1859-1864 | PMID: 33020649
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Abstract

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.

Deng Q, Han G, Puebla-Osorio N, Ma MCJ, ... Wang L, Green MR

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.



Nat Med: 29 Nov 2020; 26:1878-1887
Deng Q, Han G, Puebla-Osorio N, Ma MCJ, ... Wang L, Green MR
Nat Med: 29 Nov 2020; 26:1878-1887 | PMID: 33020644
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Abstract

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.

van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, ... van Rhijn BW, van der Heijden MS

Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma and colorectal cancer. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8 presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8 T cell activity.



Nat Med: 29 Nov 2020; 26:1839-1844
van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, ... van Rhijn BW, van der Heijden MS
Nat Med: 29 Nov 2020; 26:1839-1844 | PMID: 33046870
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Abstract

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.

Gao J, Navai N, Alhalabi O, Siefker-Radtke A, ... Goswami S, Sharma P

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.



Nat Med: 29 Nov 2020; 26:1845-1851
Gao J, Navai N, Alhalabi O, Siefker-Radtke A, ... Goswami S, Sharma P
Nat Med: 29 Nov 2020; 26:1845-1851 | PMID: 33046869
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Abstract

Acute liver failure is regulated by MYC- and microbiome-dependent programs.

Kolodziejczyk AA, Federici S, Zmora N, Mohapatra G, ... Amit I, Elinav E

Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.



Nat Med: 29 Nov 2020; 26:1899-1911
Kolodziejczyk AA, Federici S, Zmora N, Mohapatra G, ... Amit I, Elinav E
Nat Med: 29 Nov 2020; 26:1899-1911 | PMID: 33106666
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Abstract

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.

Gupta RK, Calderwood CJ, Yavlinsky A, Krutikov M, ... Noursadeghi M, Abubakar I

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.



Nat Med: 29 Nov 2020; 26:1941-1949
Gupta RK, Calderwood CJ, Yavlinsky A, Krutikov M, ... Noursadeghi M, Abubakar I
Nat Med: 29 Nov 2020; 26:1941-1949 | PMID: 33077958
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Abstract

Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.

Cerezo-Wallis D, Contreras-Alcalde M, Troulé K, Catena X, ... Olmeda D, Soengas MS

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8 T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.



Nat Med: 29 Nov 2020; 26:1865-1877
Cerezo-Wallis D, Contreras-Alcalde M, Troulé K, Catena X, ... Olmeda D, Soengas MS
Nat Med: 29 Nov 2020; 26:1865-1877 | PMID: 33077955
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Impact:
Abstract

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Burd A, Levine RL, Ruppert AS, Mims AS, ... Druker B, Byrd JC

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient\'s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.



Nat Med: 29 Nov 2020; 26:1852-1858
Burd A, Levine RL, Ruppert AS, Mims AS, ... Druker B, Byrd JC
Nat Med: 29 Nov 2020; 26:1852-1858 | PMID: 33106665
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Abstract

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season.

Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, ... Crompton PD, Portugal S

The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence.



Nat Med: 29 Nov 2020; 26:1929-1940
Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, ... Crompton PD, Portugal S
Nat Med: 29 Nov 2020; 26:1929-1940 | PMID: 33106664
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Impact:
Abstract

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

Davies RW, Fiksinski AM, Breetvelt EJ, Williams NM, ... Bearden CE, Vorstman JAS

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.



Nat Med: 29 Nov 2020; 26:1912-1918
Davies RW, Fiksinski AM, Breetvelt EJ, Williams NM, ... Bearden CE, Vorstman JAS
Nat Med: 29 Nov 2020; 26:1912-1918 | PMID: 33169016
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Impact:
Abstract

Effective control of SARS-CoV-2 transmission in Wanzhou, China.

Shi Q, Hu Y, Peng B, Tang XJ, ... Yang CY, Huang AL

The effectiveness of control measures to contain coronavirus disease 2019 (COVID-19) in Wanzhou, China was assessed. Epidemiological data were analyzed for 183 confirmed COVID-19 cases and their close contacts from five generations of transmission of severe acute respiratory syndrome coronavirus 2 throughout the entire COVID-19 outbreak in Wanzhou. Approximately 67.2% and 32.8% of cases were symptomatic and asymptomatic, respectively. Asymptomatic and presymptomatic transmission accounted for 75.9% of the total recorded transmission. The reproductive number was 1.64 (95% confidence interval: 1.16-2.40) for G1-to-G2 transmission, decreasing to 0.31-0.39 in later generations, concomitant with implementation of rigorous control measures. Substantially higher infection risk was associated with contact within 5 d after the infectors had been infected, frequent contact and ≥8 h of contact duration. The spread of COVID-19 was effectively controlled in Wanzhou by breaking the transmission chain through social distancing, extensive contact tracing, mass testing and strict quarantine of close contacts.



Nat Med: 29 Nov 2020; epub ahead of print
Shi Q, Hu Y, Peng B, Tang XJ, ... Yang CY, Huang AL
Nat Med: 29 Nov 2020; epub ahead of print | PMID: 33257893
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Abstract

Characterization of pre-existing and induced SARS-CoV-2-specific CD8 T cells.

Schulien I, Kemming J, Oberhardt V, Wild K, ... Hofmann M, Neumann-Haefelin C

Emerging data indicate that SARS-CoV-2-specific CD8 T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8 T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8 T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8 T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8 T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8 T cells exhibited functional characteristics comparable to influenza-specific CD8 T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8 T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.



Nat Med: 11 Nov 2020; epub ahead of print
Schulien I, Kemming J, Oberhardt V, Wild K, ... Hofmann M, Neumann-Haefelin C
Nat Med: 11 Nov 2020; epub ahead of print | PMID: 33184509
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Abstract

Rapid pathogen detection by metagenomic next-generation sequencing of infected body fluids.

Gu W, Deng X, Lee M, Sucu YD, ... DeRisi JL, Chiu CY

We developed a metagenomic next-generation sequencing (mNGS) test using cell-free DNA from body fluids to identify pathogens. The performance of mNGS testing of 182 body fluids from 160 patients with acute illness was evaluated using two sequencing platforms in comparison to microbiological testing using culture, 16S bacterial PCR and/or 28S-internal transcribed ribosomal gene spacer (28S-ITS) fungal PCR. Test sensitivity and specificity of detection were 79 and 91% for bacteria and 91 and 89% for fungi, respectively, by Illumina sequencing; and 75 and 81% for bacteria and 91 and 100% for fungi, respectively, by nanopore sequencing. In a case series of 12 patients with culture/PCR-negative body fluids but for whom an infectious diagnosis was ultimately established, seven (58%) were mNGS positive. Real-time computational analysis enabled pathogen identification by nanopore sequencing in a median 50-min sequencing and 6-h sample-to-answer time. Rapid mNGS testing is a promising tool for diagnosis of unknown infections from body fluids.



Nat Med: 08 Nov 2020; epub ahead of print
Gu W, Deng X, Lee M, Sucu YD, ... DeRisi JL, Chiu CY
Nat Med: 08 Nov 2020; epub ahead of print | PMID: 33169017
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Abstract

Wearable sensor data and self-reported symptoms for COVID-19 detection.

Quer G, Radin JM, Gadaleta M, Baca-Motes K, ... Topol EJ, Steinhubl SR

Traditional screening for COVID-19 typically includes survey questions about symptoms and travel history, as well as temperature measurements. Here, we explore whether personal sensor data collected over time may help identify subtle changes indicating an infection, such as in patients with COVID-19. We have developed a smartphone app that collects smartwatch and activity tracker data, as well as self-reported symptoms and diagnostic testing results, from individuals in the United States, and have assessed whether symptom and sensor data can differentiate COVID-19 positive versus negative cases in symptomatic individuals. We enrolled 30,529 participants between 25 March and 7 June 2020, of whom 3,811 reported symptoms. Of these symptomatic individuals, 54 reported testing positive and 279 negative for COVID-19. We found that a combination of symptom and sensor data resulted in an area under the curve (AUC) of 0.80 (interquartile range (IQR): 0.73-0.86) for discriminating between symptomatic individuals who were positive or negative for COVID-19, a performance that is significantly better (P < 0.01) than a model that considers symptoms alone (AUC = 0.71; IQR: 0.63-0.79). Such continuous, passively captured data may be complementary to virus testing, which is generally a one-off or infrequent sampling assay.



Nat Med: 28 Oct 2020; epub ahead of print
Quer G, Radin JM, Gadaleta M, Baca-Motes K, ... Topol EJ, Steinhubl SR
Nat Med: 28 Oct 2020; epub ahead of print | PMID: 33122860
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Impact:
Abstract

Modeling COVID-19 scenarios for the United States.



We use COVID-19 case and mortality data from 1 February 2020 to 21 September 2020 and a deterministic SEIR (susceptible, exposed, infectious and recovered) compartmental framework to model possible trajectories of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the effects of non-pharmaceutical interventions in the United States at the state level from 22 September 2020 through 28 February 2021. Using this SEIR model, and projections of critical driving covariates (pneumonia seasonality, mobility, testing rates and mask use per capita), we assessed scenarios of social distancing mandates and levels of mask use. Projections of current non-pharmaceutical intervention strategies by state-with social distancing mandates reinstated when a threshold of 8 deaths per million population is exceeded (reference scenario)-suggest that, cumulatively, 511,373 (469,578-578,347) lives could be lost to COVID-19 across the United States by 28 February 2021. We find that achieving universal mask use (95% mask use in public) could be sufficient to ameliorate the worst effects of epidemic resurgences in many states. Universal mask use could save an additional 129,574 (85,284-170,867) lives from September 22, 2020 through the end of February 2021, or an additional 95,814 (60,731-133,077) lives assuming a lesser adoption of mask wearing (85%), when compared to the reference scenario.



Nat Med: 22 Oct 2020; epub ahead of print
Nat Med: 22 Oct 2020; epub ahead of print | PMID: 33097835
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Abstract

A global survey of potential acceptance of a COVID-19 vaccine.

Lazarus JV, Ratzan SC, Palayew A, Gostin LO, ... Kimball S, El-Mohandes A

Several coronavirus disease 2019 (COVID-19) vaccines are currently in human trials. In June 2020, we surveyed 13,426 people in 19 countries to determine potential acceptance rates and factors influencing acceptance of a COVID-19 vaccine. Of these, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine, and 61.4% reported that they would accept their employer\'s recommendation to do so. Differences in acceptance rates ranged from almost 90% (in China) to less than 55% (in Russia). Respondents reporting higher levels of trust in information from government sources were more likely to accept a vaccine and take their employer\'s advice to do so.



Nat Med: 19 Oct 2020; epub ahead of print
Lazarus JV, Ratzan SC, Palayew A, Gostin LO, ... Kimball S, El-Mohandes A
Nat Med: 19 Oct 2020; epub ahead of print | PMID: 33082575
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Impact:

This program is still in alpha version.