Journal: Nat Med

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Abstract

COVID-19 dynamics after a national immunization program in Israel.

Rossman H, Shilo S, Meir T, Gorfine M, Shalit U, Segal E
Studies on the real-life effect of the BNT162b2 vaccine for Coronavirus Disease 2019 (COVID-19) prevention are urgently needed. In this study, we conducted a retrospective analysis of data from the Israeli Ministry of Health collected between 28 August 2020 and 24 February 2021. We studied the temporal dynamics of the number of new COVID-19 cases and hospitalizations after the vaccination campaign, which was initiated on 20 December 2020. To distinguish the possible effects of the vaccination on cases and hospitalizations from other factors, including a third lockdown implemented on 8 January 2021, we performed several comparisons: (1) individuals aged 60 years and older prioritized to receive the vaccine first versus younger age groups; (2) the January lockdown versus the September lockdown; and (3) early-vaccinated versus late-vaccinated cities. A larger and earlier decrease in COVID-19 cases and hospitalization was observed in individuals older than 60 years, followed by younger age groups, by the order of vaccination prioritization. This pattern was not observed in the previous lockdown and was more pronounced in early-vaccinated cities. Our analysis demonstrates the real-life effect of a national vaccination campaign on the pandemic dynamics.



Nat Med: 18 Apr 2021; epub ahead of print
Rossman H, Shilo S, Meir T, Gorfine M, Shalit U, Segal E
Nat Med: 18 Apr 2021; epub ahead of print | PMID: 33875890
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Abstract

Modeling vaccination rollouts, SARS-CoV-2 variants and the requirement for non-pharmaceutical interventions in Italy.

Giordano G, Colaneri M, Di Filippo A, Blanchini F, ... Colaneri P, Bruno R
Despite progress in clinical care for patients with coronavirus disease 2019 (COVID-19)1, population-wide interventions are still crucial to manage the pandemic, which has been aggravated by the emergence of new, highly transmissible variants. In this study, we combined the SIDARTHE model2, which predicts the spread of SARS-CoV-2 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs. Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants and different enforced countermeasures, including the alternation of opening and closure phases. Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher effect on the epidemic evolution than vaccination alone, advocating for the need to keep NPIs in place during the first phase of the vaccination campaign. Our model predicts that, from April 2021 to January 2022, in a scenario with no vaccine rollout and weak NPIs ([Formula: see text] = 1.27), as many as 298,000 deaths associated with COVID-19 could occur. However, fast vaccination rollouts could reduce mortality to as few as 51,000 deaths. Implementation of restrictive NPIs ([Formula: see text] = 0.9) could reduce COVID-19 deaths to 30,000 without vaccinating the population and to 18,000 with a fast rollout of vaccines. We also show that, if intermittent open-close strategies are adopted, implementing a closing phase first could reduce deaths (from 47,000 to 27,000 with slow vaccine rollout) and healthcare system costs, without substantive aggravation of socioeconomic losses.



Nat Med: 15 Apr 2021; epub ahead of print
Giordano G, Colaneri M, Di Filippo A, Blanchini F, ... Colaneri P, Bruno R
Nat Med: 15 Apr 2021; epub ahead of print | PMID: 33864052
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Abstract

Triage-driven diagnosis of Barrett\'s esophagus for early detection of esophageal adenocarcinoma using deep learning.

Gehrung M, Crispin-Ortuzar M, Berman AG, O\'Donovan M, Fitzgerald RC, Markowetz F
Deep learning methods have been shown to achieve excellent performance on diagnostic tasks, but how to optimally combine them with expert knowledge and existing clinical decision pathways is still an open challenge. This question is particularly important for the early detection of cancer, where high-volume workflows may benefit from (semi-)automated analysis. Here we present a deep learning framework to analyze samples of the Cytosponge-TFF3 test, a minimally invasive alternative to endoscopy, for detecting Barrett\'s esophagus, which is the main precursor of esophageal adenocarcinoma. We trained and independently validated the framework on data from two clinical trials, analyzing a combined total of 4,662 pathology slides from 2,331 patients. Our approach exploits decision patterns of gastrointestinal pathologists to define eight triage classes of varying priority for manual expert review. By substituting manual review with automated review in low-priority classes, we can reduce pathologist workload by 57% while matching the diagnostic performance of experienced pathologists.



Nat Med: 14 Apr 2021; epub ahead of print
Gehrung M, Crispin-Ortuzar M, Berman AG, O'Donovan M, Fitzgerald RC, Markowetz F
Nat Med: 14 Apr 2021; epub ahead of print | PMID: 33859411
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Abstract

Vaccine development for emerging infectious diseases.

Excler JL, Saville M, Berkley S, Kim JH
Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics may offer some mutually beneficial lessons. The unprecedented scale and rapidity of dissemination of recent emerging infectious diseases pose new challenges for vaccine developers, regulators, health authorities and political constituencies. Vaccine manufacturing and distribution are complex and challenging. While speed is essential, clinical development to emergency use authorization and licensure, pharmacovigilance of vaccine safety and surveillance of virus variants are also critical. Access to vaccines and vaccination needs to be prioritized in low- and middle-income countries. The combination of these factors will weigh heavily on the ultimate success of efforts to bring the current and any future emerging infectious disease pandemics to a close.



Nat Med: 11 Apr 2021; epub ahead of print
Excler JL, Saville M, Berkley S, Kim JH
Nat Med: 11 Apr 2021; epub ahead of print | PMID: 33846611
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Abstract

Integration of genomic sequencing into the response to the Ebola virus outbreak in Nord Kivu, Democratic Republic of the Congo.

Kinganda-Lusamaki E, Black A, Mukadi DB, Hadfield J, ... Bedford T, Tamfum JM
On 1 August 2018, the Democratic Republic of the Congo (DRC) declared its tenth Ebola virus disease (EVD) outbreak. To aid the epidemiologic response, the Institut National de Recherche Biomédicale (INRB) implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis and dissemination of genomic epidemiologic results to frontline public health workers. We report 744 new genomes sampled between 27 July 2018 and 27 April 2020 generated by this surveillance effort. Together with previously available sequence data (n = 48 genomes), these data represent almost 24% of all laboratory-confirmed Ebola virus (EBOV) infections in DRC in the period analyzed. We inferred spatiotemporal transmission dynamics from the genomic data as new sequences were generated, and disseminated the results to support epidemiologic response efforts. Here we provide an overview of how this genomic surveillance system functioned, present a full phylodynamic analysis of 792 Ebola genomes from the Nord Kivu outbreak and discuss how the genomic surveillance data informed response efforts and public health decision making.



Nat Med: 11 Apr 2021; epub ahead of print
Kinganda-Lusamaki E, Black A, Mukadi DB, Hadfield J, ... Bedford T, Tamfum JM
Nat Med: 11 Apr 2021; epub ahead of print | PMID: 33846610
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Abstract

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Gaziano L, Giambartolomei C, Pereira AC, Gaulton A, ... Casas JP, VA Million Veteran Program COVID-19 Science Initiative
Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.



Nat Med: 08 Apr 2021; epub ahead of print
Gaziano L, Giambartolomei C, Pereira AC, Gaulton A, ... Casas JP, VA Million Veteran Program COVID-19 Science Initiative
Nat Med: 08 Apr 2021; epub ahead of print | PMID: 33837377
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Abstract

A framework for microbiome science in public health.

Wilkinson JE, Franzosa EA, Everett C, Li C, ... Garrett WS, Huttenhower C
Human microbiome science has advanced rapidly and reached a scale at which basic biology, clinical translation and population health are increasingly integrated. It is thus now possible for public health researchers, practitioners and policymakers to take specific action leveraging current and future microbiome-based opportunities and best practices. Here we provide an outline of considerations for research, education, interpretation and scientific communication concerning the human microbiome and public health. This includes guidelines for population-scale microbiome study design; necessary physical platforms and analysis methods; integration into public health areas such as epidemiology, nutrition, chronic disease, and global and environmental health; entrepreneurship and technology transfer; and educational curricula. Particularly in the near future, there are both opportunities for the incorporation of microbiome-based technologies into public health practice, and a growing need for policymaking and regulation around related areas such as prebiotic and probiotic supplements, novel live-cell therapies and fecal microbiota transplants.



Nat Med: 04 Apr 2021; epub ahead of print
Wilkinson JE, Franzosa EA, Everett C, Li C, ... Garrett WS, Huttenhower C
Nat Med: 04 Apr 2021; epub ahead of print | PMID: 33820996
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Abstract

Integrative microbiomics in bronchiectasis exacerbations.

Mac Aogáin M, Narayana JK, Tiew PY, Ali NABM, ... Chalmers JD, Chotirmall SH
Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.



Nat Med: 04 Apr 2021; epub ahead of print
Mac Aogáin M, Narayana JK, Tiew PY, Ali NABM, ... Chalmers JD, Chotirmall SH
Nat Med: 04 Apr 2021; epub ahead of print | PMID: 33820995
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Abstract

Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2.

Ebinger JE, Fert-Bober J, Printsev I, Wu M, ... Cheng S, Sobhani K
In a cohort of BNT162b2 (Pfizer-BioNTech) mRNA vaccine recipients (n = 1,090), we observed that spike-specific IgG antibody levels and ACE2 antibody binding inhibition responses elicited by a single vaccine dose in individuals with prior SARS-CoV-2 infection (n = 35) were similar to those seen after two doses of vaccine in individuals without prior infection (n = 228). Post-vaccine symptoms were more prominent for those with prior infection after the first dose, but symptomology was similar between groups after the second dose.



Nat Med: 31 Mar 2021; epub ahead of print
Ebinger JE, Fert-Bober J, Printsev I, Wu M, ... Cheng S, Sobhani K
Nat Med: 31 Mar 2021; epub ahead of print | PMID: 33795870
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Abstract

Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report.

Cideciyan AV, Jacobson SG, Ho AC, Garafalo AV, ... Schwartz MR, Girach A
Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969 ) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors.



Nat Med: 31 Mar 2021; epub ahead of print
Cideciyan AV, Jacobson SG, Ho AC, Garafalo AV, ... Schwartz MR, Girach A
Nat Med: 31 Mar 2021; epub ahead of print | PMID: 33795869
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Abstract

Altered perivascular fibroblast activity precedes ALS disease onset.

Månberg A, Skene N, Sanders F, Trusohamn M, ... Nilsson P, Lewandowski SA
Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.



Nat Med: 30 Mar 2021; 27:640-646
Månberg A, Skene N, Sanders F, Trusohamn M, ... Nilsson P, Lewandowski SA
Nat Med: 30 Mar 2021; 27:640-646 | PMID: 33859435
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Abstract

Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine.

Levine-Tiefenbrun M, Yelin I, Katz R, Herzel E, ... Chodick G, Kishony R
Beyond their substantial protection of individual vaccinees, coronavirus disease 2019 (COVID-19) vaccines might reduce viral load in breakthrough infection and thereby further suppress onward transmission. In this analysis of a real-world dataset of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results after inoculation with the BNT162b2 messenger RNA vaccine, we found that the viral load was substantially reduced for infections occurring 12-37 d after the first dose of vaccine. These reduced viral loads hint at a potentially lower infectiousness, further contributing to vaccine effect on virus spread.



Nat Med: 28 Mar 2021; epub ahead of print
Levine-Tiefenbrun M, Yelin I, Katz R, Herzel E, ... Chodick G, Kishony R
Nat Med: 28 Mar 2021; epub ahead of print | PMID: 33782619
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Abstract

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.

Planas D, Bruel T, Grzelak L, Guivel-Benhassine F, ... Prazuck T, Schwartz O
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.



Nat Med: 25 Mar 2021; epub ahead of print
Planas D, Bruel T, Grzelak L, Guivel-Benhassine F, ... Prazuck T, Schwartz O
Nat Med: 25 Mar 2021; epub ahead of print | PMID: 33772244
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Abstract

SARS-CoV-2 infection of the oral cavity and saliva.

Huang N, Pérez P, Kato T, Mikami Y, ... Warner BM, Byrd KM
Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.



Nat Med: 24 Mar 2021; epub ahead of print
Huang N, Pérez P, Kato T, Mikami Y, ... Warner BM, Byrd KM
Nat Med: 24 Mar 2021; epub ahead of print | PMID: 33767405
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Abstract

Post-acute COVID-19 syndrome.

Nalbandian A, Sehgal K, Gupta A, Madhavan MV, ... Landry DW, Wan EY
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.



Nat Med: 21 Mar 2021; epub ahead of print
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, ... Landry DW, Wan EY
Nat Med: 21 Mar 2021; epub ahead of print | PMID: 33753937
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Abstract

Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells.

Cromer MK, Camarena J, Martin RM, Lesch BJ, ... Dever DP, Porteus MH
β-Thalassemia pathology is due not only to loss of β-globin (HBB), but also to erythrotoxic accumulation and aggregation of the β-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing β-thalassemia.



Nat Med: 17 Mar 2021; epub ahead of print
Cromer MK, Camarena J, Martin RM, Lesch BJ, ... Dever DP, Porteus MH
Nat Med: 17 Mar 2021; epub ahead of print | PMID: 33737751
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Impact:
Abstract

Assessment of medication self-administration using artificial intelligence.

Zhao M, Hoti K, Wang H, Raghu A, Katabi D
Errors in medication self-administration (MSA) lead to poor treatment adherence, increased hospitalizations and higher healthcare costs. These errors are particularly common when medication delivery involves devices such as inhalers or insulin pens. We present a contactless and unobtrusive artificial intelligence (AI) framework that can detect and monitor MSA errors by analyzing the wireless signals in the patient\'s home, without the need for physical contact. The system was developed by observing self-administration conducted by volunteers and evaluated by comparing its prediction with human annotations. Findings from this study demonstrate that our approach can automatically detect when patients use their inhalers (area under the curve (AUC) = 0.992) or insulin pens (AUC = 0.967), and assess whether patients follow the appropriate steps for using these devices (AUC = 0.952). The work shows the potential of leveraging AI-based solutions to improve medication safety with minimal overhead for patients and health professionals.



Nat Med: 17 Mar 2021; epub ahead of print
Zhao M, Hoti K, Wang H, Raghu A, Katabi D
Nat Med: 17 Mar 2021; epub ahead of print | PMID: 33737750
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Abstract

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.

Villar J, Gunier RB, Tshivuila-Matala COO, Rauch SA, ... Papageorghiou AT, Kennedy SH
Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks\' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks\' gestation.



Nat Med: 17 Mar 2021; epub ahead of print
Villar J, Gunier RB, Tshivuila-Matala COO, Rauch SA, ... Papageorghiou AT, Kennedy SH
Nat Med: 17 Mar 2021; epub ahead of print | PMID: 33737749
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Impact:
Abstract

Attributes and predictors of long COVID.

Sudre CH, Murray B, Varsavsky T, Graham MS, ... Spector T, Steves CJ
Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called \'long COVID\', are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.



Nat Med: 09 Mar 2021; epub ahead of print
Sudre CH, Murray B, Varsavsky T, Graham MS, ... Spector T, Steves CJ
Nat Med: 09 Mar 2021; epub ahead of print | PMID: 33692530
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Impact:
Abstract

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies.

Chen RE, Zhang X, Case JB, Winkler ES, ... Shi PY, Diamond MS
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.



Nat Med: 03 Mar 2021; epub ahead of print
Chen RE, Zhang X, Case JB, Winkler ES, ... Shi PY, Diamond MS
Nat Med: 03 Mar 2021; epub ahead of print | PMID: 33664494
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Abstract

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.

Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, ... Bhiman JN, Moore PL
SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines.



Nat Med: 01 Mar 2021; epub ahead of print
Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, ... Bhiman JN, Moore PL
Nat Med: 01 Mar 2021; epub ahead of print | PMID: 33654292
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Impact:
Abstract

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys.

Tao Y, Vermilyea SC, Zammit M, Lu J, ... Emborg ME, Zhang SC
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson\'s disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.



Nat Med: 28 Feb 2021; epub ahead of print
Tao Y, Vermilyea SC, Zammit M, Lu J, ... Emborg ME, Zhang SC
Nat Med: 28 Feb 2021; epub ahead of print | PMID: 33649496
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Impact:
Abstract

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

Zhou S, Butler-Laporte G, Nakanishi T, Morrison DR, ... Kaufmann DE, Richards JB
To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.



Nat Med: 24 Feb 2021; epub ahead of print
Zhou S, Butler-Laporte G, Nakanishi T, Morrison DR, ... Kaufmann DE, Richards JB
Nat Med: 24 Feb 2021; epub ahead of print | PMID: 33633408
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Abstract

Malaria is a cause of iron deficiency in African children.

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, ... Williams TN, Atkinson SH
Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.



Nat Med: 21 Feb 2021; epub ahead of print
Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, ... Williams TN, Atkinson SH
Nat Med: 21 Feb 2021; epub ahead of print | PMID: 33619371
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Abstract

Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial.

Nakatsuji T, Hata TR, Tong Y, Cheng JY, ... Leung DYM, Gallo RL
Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.



Nat Med: 21 Feb 2021; epub ahead of print
Nakatsuji T, Hata TR, Tong Y, Cheng JY, ... Leung DYM, Gallo RL
Nat Med: 21 Feb 2021; epub ahead of print | PMID: 33619370
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Abstract

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.

Da Vià MC, Dietrich O, Truger M, Arampatzi P, ... Saliba AE, Rasche L
B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.



Nat Med: 21 Feb 2021; epub ahead of print
Da Vià MC, Dietrich O, Truger M, Arampatzi P, ... Saliba AE, Rasche L
Nat Med: 21 Feb 2021; epub ahead of print | PMID: 33619368
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Abstract

Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera.

Xie X, Liu Y, Liu J, Zhang X, ... Dormitzer PR, Shi PY
We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.



Nat Med: 07 Feb 2021; epub ahead of print
Xie X, Liu Y, Liu J, Zhang X, ... Dormitzer PR, Shi PY
Nat Med: 07 Feb 2021; epub ahead of print | PMID: 33558724
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This program is still in alpha version.