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, James B. Bussel,
Published: 9 June 2021
Nature Medicine, Volume 27, pp 1145-1146; doi:10.1038/s41591-021-01419-1

Abstract:
A prospective cohort analysis finds a link between the ChAdOx1 vaccine and an autoimmune disorder known as immune thrombocytopenia—but questions remain and causality is yet to be established.
C. R. Simpson, T. Shi, E. Vasileiou, , S. Kerr, E. Moore, C. McCowan, U. Agrawal, , L. D. Ritchie, et al.
Published: 9 June 2021
Nature Medicine, Volume 27, pp 1-8; doi:10.1038/s41591-021-01408-4

Abstract:
Reports of ChAdOx1 vaccine–associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0–27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41–13.83), with an estimated incidence of 1.13 (0.62–1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29–3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12–1.34) 0–27 d after vaccination, with an SCCS RR of 0.97 (0.93–1.02). For hemorrhagic events 0–27 d after vaccination, the aRR was 1.48 (1.12–1.96), with an SCCS RR of 0.95 (0.82–1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.
Nila J. Dharan, Paul Yeh, Mark Bloch, Miriam M. Yeung, David Baker, Jerick Guinto, Norman Roth, Sarah Ftouni, Katherine Ognenovska, Don Smith, et al.
Published: 7 June 2021
Nature Medicine, Volume 27, pp 1006-1011; doi:10.1038/s41591-021-01357-y

Abstract:
People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1–5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6–10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34–3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection. In a prospective cohort study, HIV-positive participants have a higher incidence of clonal hematopoiesis than HIV-negative ones, implicating clonal hematopoiesis in the increased risks of individuals with HIV for malignancy and cardiovascular disease.
Nili Furer, Nathali Kaushansky,
Published: 7 June 2021
Nature Medicine, Volume 27, pp 949-950; doi:10.1038/s41591-021-01396-5

Abstract:
Clonal hematopoiesis can exist as both a driver and a consequence of inflammatory dysregulation.
Seyedeh M. Zekavat, Shu-Hong Lin, Alexander G. Bick, Aoxing Liu, Kaavya Paruchuri, Chen Wang, , Yixuan Ye, , Xiaoxi Liu, et al.
Published: 7 June 2021
by 10.1038
Nature Medicine, Volume 27, pp 1012-1024; doi:10.1038/s41591-021-01371-0

The publisher has not yet granted permission to display this abstract.
Published: 3 June 2021
Nature Medicine, Volume 27, pp 954-963; doi:10.1038/s41591-021-01382-x

Abstract:
Biomarkers for neurodegenerative diseases are needed to improve the diagnostic workup in the clinic but also to facilitate the development and monitoring of effective disease-modifying therapies. Positron emission tomography methods detecting amyloid-β and tau pathology in Alzheimer’s disease have been increasingly used to improve the design of clinical trials and observational studies. In recent years, easily accessible and cost-effective blood-based biomarkers detecting the same Alzheimer’s disease pathologies have been developed, which might revolutionize the diagnostic workup of Alzheimer’s disease globally. Relevant biomarkers for α-synuclein pathology in Parkinson’s disease are also emerging, as well as blood-based markers of general neurodegeneration and glial activation. This review presents an overview of the latest advances in the field of biomarkers for neurodegenerative diseases. Future directions are discussed regarding implementation of novel biomarkers in clinical practice and trials. As the development of biomarkers for neurodegenerative diseases advances, new opportunities arise for their implementation in clinical practice and trials.
Theodore J. Morley, Lide Han, Victor M. Castro, Jonathan Morra, Roy H. Perlis, Nancy J. Cox, Lisa Bastarache,
Published: 3 June 2021
Nature Medicine, Volume 27, pp 1097-1104; doi:10.1038/s41591-021-01356-z

Abstract:
Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision–recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs. Machine learning of electronic health records identifies individuals with a high suspicion of a wide range of genetic diseases and prioritizes those individuals for genetic testing.
Karen O’Leary
Published: 3 June 2021
Nature Medicine; doi:10.1038/d41591-021-00037-1

Abstract:
Critically ill patients with COVID-19 in Africa are at higher risk of death than those elsewhere. Critically ill patients with COVID-19 in Africa are at higher risk of death than those elsewhere.
, Leigh Conroy, Michael C. Tjong, Tim Craig, Andrew Bayley, Charles Catton, Mary Gospodarowicz, Joelle Helou, Naghmeh Isfahanian, Vickie Kong, et al.
Published: 3 June 2021
Nature Medicine, Volume 27, pp 999-1005; doi:10.1038/s41591-021-01359-w

Abstract:
Machine learning (ML) holds great promise for impacting healthcare delivery; however, to date most methods are tested in ‘simulated’ environments that cannot recapitulate factors influencing real-world clinical practice. We prospectively deployed and evaluated a random forest algorithm for therapeutic curative-intent radiation therapy (RT) treatment planning for prostate cancer in a blinded, head-to-head study with full integration into the clinical workflow. ML- and human-generated RT treatment plans were directly compared in a retrospective simulation with retesting (n = 50) and a prospective clinical deployment (n = 50) phase. Consistently throughout the study phases, treating physicians assessed ML- and human-generated RT treatment plans in a blinded manner following a priori defined standardized criteria and peer review processes, with the selected RT plan in the prospective phase delivered for patient treatment. Overall, 89% of ML-generated RT plans were considered clinically acceptable and 72% were selected over human-generated RT plans in head-to-head comparisons. RT planning using ML reduced the median time required for the entire RT planning process by 60.1% (118 to 47 h). While ML RT plan acceptability remained stable between the simulation and deployment phases (92 versus 86%), the number of ML RT plans selected for treatment was significantly reduced (83 versus 61%, respectively). These findings highlight that retrospective or simulated evaluation of ML methods, even under expert blinded review, may not be representative of algorithm acceptance in a real-world clinical setting when patient care is at stake. An artificial intelligence system prospectively deployed to design radiation therapy plans for patients with prostate cancer illustrates the real-world impact of machine learning in clinical practice and identifies factors influencing human–algorithm interaction
Correction
, Saji Oommen, , Sean C. Goetsch, David R. Pease, Rhianna S. Sundsbak, , Mingming Sun, Han Sun, Hidehito Kuroyanagi, et al.
Published: 2 June 2021
Nature Medicine pp 1-1; doi:10.1038/s41591-021-01412-8

Correction
, Nathan Skene, Folkert Sanders, Marta Trusohamn, Julia Remnestål, Anna Szczepińska, Inci Sevval Aksoylu, Peter Lönnerberg, Lwaki Ebarasi, Stefan Wouters, et al.
Published: 2 June 2021
Nature Medicine pp 1-1; doi:10.1038/s41591-021-01414-6

Correction
Sebastian M. Gygli, Chloé Loiseau, Levan Jugheli, Natia Adamia, , Miriam Reinhard, , Sonia Borrell, Rusudan Aspindzelashvili, Nino Maghradze, et al.
Published: 1 June 2021
Nature Medicine pp 1-1; doi:10.1038/s41591-021-01417-3

Correction
Madaiah Puttaraju, Michaela Jackson, Stephanie Klein, Asaf Shilo, C. Frank Bennett, Leslie Gordon, Frank Rigo,
Published: 1 June 2021
Nature Medicine pp 1-1; doi:10.1038/s41591-021-01415-5

Payam Mohassel, Sandra Donkervoort, Museer A. Lone, Matthew Nalls, Kenneth Gable, Sita D. Gupta, A. Reghan Foley, Ying Hu, Jonas Alex Morales Saute, Ana Lucila Moreira, et al.
Published: 31 May 2021
Nature Medicine, Volume 27, pp 1197-1204; doi:10.1038/s41591-021-01346-1

Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease. Clinical and genetic evaluation of individuals with childhood-onset amyotrophic lateral sclerosis identifies a new monogenic cause for early-onset ALS and proposes a specific metabolic mechanism leading to motor neuron disease via sphingolipid excess.
Mike May
Published: 31 May 2021
Nature Medicine, Volume 27, pp 930-932; doi:10.1038/s41591-021-01393-8

Abstract:
MRNA vaccines are now in the limelight as a key tool for tackling COVID-19, but the technology was originally developed for other diseases, such as cancer, that researchers are now hoping to treat.
Karen O’Leary
Published: 27 May 2021
Nature Medicine; doi:10.1038/d41591-021-00036-2

Abstract:
A brain implant in a paralyzed person can decode neuronal activity into accurate text communication. A brain implant in a paralyzed person can decode neuronal activity into accurate text communication.
Correction
Laura K. Donovan, Alberto Delaidelli, Sujith K. Joseph, Kevin Bielamowicz, , Borja L. Holgado, Alex Manno, Dilakshan Srikanthan, Ahmed Z. Gad, , et al.
Published: 27 May 2021
Nature Medicine, Volume 27, pp 1117-1120; doi:10.1038/s41591-021-01362-1

Karen O’Leary
Published: 27 May 2021
Nature Medicine; doi:10.1038/d41591-021-00035-3

Abstract:
Two studies report that antiseptic mouthwash does not reduce the incidence of oral sexually transmitted infections. Two studies report that antiseptic mouthwash does not reduce the incidence of oral sexually transmitted infections.
Correction
Carole H. Sudre, , Thomas Varsavsky, , Rose S. Penfold, , , Kerstin Klaser, Michela Antonelli, Liane S. Canas, et al.
Published: 27 May 2021
Nature Medicine, Volume 27, pp 1116-1116; doi:10.1038/s41591-021-01361-2

Correction
, , Barbara H. Stokes, Jean-Louis Mangala Ndikumana, Marian Warsame, Noella Umulisa, Daniel Ngamije, Tharcisse Munyaneza, Jean-Baptiste Mazarati, Kaendi Munguti, et al.
Published: 27 May 2021
Nature Medicine, Volume 27, pp 1113-1115; doi:10.1038/s41591-021-01365-y

Kaitlin H. Wade, , Audrey Melvin, Warren Pan, , , Kara Rainbow, Jian-Hua Chen, Katie Duckett, XiaoMing Liu, et al.
Published: 27 May 2021
Nature Medicine, Volume 27, pp 1088-1096; doi:10.1038/s41591-021-01349-y

Abstract:
Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m−2 (95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity. Analysis of mutations in MC4R and associated anthropometric phenotypes in the ALSPAC birth cohort reveals a prevalence of heterozygous loss of function of 0.30% and provides evidence that these mutations are associated with substantial excess adiposity in early life.
Jasdeep Singh, , Nasreen Z. Ehtesham, , Seyed E. Hasnain
Published: 27 May 2021
Nature Medicine pp 1-3; doi:10.1038/s41591-021-01397-4

Lewis Au, Annika Fendler, Scott T. C. Shepherd, Karolina Rzeniewicz, Maddalena Cerrone, Fiona Byrne, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, John Shon, et al.
Published: 26 May 2021
Nature Medicine pp 1-5; doi:10.1038/s41591-021-01387-6

Abstract:
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.
, Valdinete Nascimento, Victor Costa de Souza, André De Lima Corado, Fernanda Nascimento, George Silva, Ágatha Costa, Débora Duarte, Karina Pessoa, Matilde Mejía, et al.
Published: 25 May 2021
Nature Medicine, Volume 27, pp 1230-1238; doi:10.1038/s41591-021-01378-7

Abstract:
The northern state of Amazonas is among the regions in Brazil most heavily affected by the COVID-19 epidemic and has experienced two exponentially growing waves, in early and late 2020. Through a genomic epidemiology study based on 250 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from different Amazonas municipalities sampled between March 2020 and January 2021, we reveal that the first exponential growth phase was driven mostly by the dissemination of lineage B.1.195, which was gradually replaced by lineage B.1.1.28 between May and June 2020. The second wave coincides with the emergence of the variant of concern (VOC) P.1, which evolved from a local B.1.1.28 clade in late November 2020 and replaced the parental lineage in <2 months. Our findings support the conclusion that successive lineage replacements in Amazonas were driven by a complex combination of variable levels of social distancing measures and the emergence of a more transmissible VOC P.1 virus. These data provide insights to understanding the mechanisms underlying the COVID-19 epidemic waves and the risk of dissemination of SARS-CoV-2 VOC P.1 in Brazil and, potentially, worldwide. Analysis of circulating SARS-CoV-2 viruses during the first and second waves of COVID-19 in Amazonas, Brazil, shows successive lineage replacements led to predominance of the variant of concern P.1 and are associated with variable levels of social distancing.
Sebastian M. Gygli, Chloé Loiseau, Levan Jugheli, Natia Adamia, , Miriam Reinhard, , Sonia Borrell, Rusudan Aspindzelashvili, Nino Maghradze, et al.
Published: 24 May 2021
Nature Medicine pp 1-7; doi:10.1038/s41591-021-01358-x

Abstract:
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual deaths due to antimicrobial resistance1. Drug resistance-conferring mutations frequently cause fitness costs in bacteria2–5. Experimental work indicates that these drug resistance-related fitness costs might be mitigated by compensatory mutations6–10. However, the clinical relevance of compensatory evolution remains poorly understood. Here we show that, in the country of Georgia, during a 6-year nationwide study, 63% of MDR-TB was due to patient-to-patient transmission. Compensatory mutations and patient incarceration were independently associated with transmission. Furthermore, compensatory mutations were overrepresented among isolates from incarcerated individuals that also frequently spilled over into the non-incarcerated population. As a result, up to 31% of MDR-TB in Georgia was directly or indirectly linked to prisons. We conclude that prisons fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of fitness-compensated strains with high transmission potential. Understanding the ecological drivers of highly transmissible, multidrug-resistant Mycobacterium tuberculosis.
, Harriet de Wit
Published: 24 May 2021
Nature Medicine, Volume 27, pp 950-951; doi:10.1038/s41591-021-01385-8

Abstract:
A phase 3 study shows that MDMA may be a promising treatment for PTSD, which will require a shift in how this drug is perceived.
Published: 24 May 2021
Nature Medicine, Volume 27, pp 939-939; doi:10.1038/s41591-021-01380-z

Abstract:
Oligonucleotides offer therapeutic potential for patients with genetic disorders carrying unique mutations, but developing individualized therapies is not supported by the current process for drug development.
, Elise Boulanger-Scemama, Chloé Pagot, Angelo Arleo, Francesco Galluppi, Joseph N. Martel, Simona Degli Esposti, , Jean-Baptiste de Saint Aubert, Caroline de Montleau, et al.
Published: 24 May 2021
by 10.1038
Nature Medicine pp 1-7; doi:10.1038/s41591-021-01351-4

The publisher has not yet granted permission to display this abstract.
, Kaysie Brown, Ron Waldman
Published: 24 May 2021
Nature Medicine, Volume 27, pp 934-934; doi:10.1038/s41591-021-01374-x

, , Ryan Runge, Daniel Witt, Jennifer L. Hicks, , Xiao Li, Amir Bahmani, Scott L. Delp, , et al.
Published: 24 May 2021
Nature Medicine, Volume 27, pp 1105-1112; doi:10.1038/s41591-021-01339-0

Abstract:
Vital signs, including heart rate and body temperature, are useful in detecting or monitoring medical conditions, but are typically measured in the clinic and require follow-up laboratory testing for more definitive diagnoses. Here we examined whether vital signs as measured by consumer wearable devices (that is, continuously monitored heart rate, body temperature, electrodermal activity and movement) can predict clinical laboratory test results using machine learning models, including random forest and Lasso models. Our results demonstrate that vital sign data collected from wearables give a more consistent and precise depiction of resting heart rate than do measurements taken in the clinic. Vital sign data collected from wearables can also predict several clinical laboratory measurements with lower prediction error than predictions made using clinically obtained vital sign measurements. The length of time over which vital signs are monitored and the proximity of the monitoring period to the date of prediction play a critical role in the performance of the machine learning models. These results demonstrate the value of commercial wearable devices for continuous and longitudinal assessment of physiological measurements that today can be measured only with clinical laboratory tests. Data from wearable sensors, including heart rate, body temperature, electrodermal activity and movement, can predict clinical laboratory measurements, with highest accuracy for hematological tests such as hematocrit.
Published: 24 May 2021
Nature Medicine, Volume 27, pp 929-929; doi:10.1038/s41591-021-01400-y

Abstract:
The surge in COVID-19 cases in India and Brazil highlights the need to improve vaccine manufacturing capacity and investment in public health at the local level.
, Pontus Tideman, Nicholas Cullen, , , , Erik Stomrud, , Niklas Mattsson-Carlgren, , et al.
Published: 24 May 2021
Nature Medicine, Volume 27, pp 1034-1042; doi:10.1038/s41591-021-01348-z

Abstract:
A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90–0.91 in both cohorts. Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials. Plasma P-tau, in combination with clinical measures, predicts future Alzheimer’s disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists.
Correction
, Jordan R. Barrett, Sandra Belij-Rammerstorfer, , Rebecca Makinson, Richard Morter, , , Duncan Bellamy, Mustapha Bittaye, et al.
Published: 21 May 2021
Nature Medicine, Volume 27, pp 1116-1116; doi:10.1038/s41591-021-01363-0

, Gloria Igihozo, Laura Wotton
Published: 20 May 2021
Nature Medicine, Volume 27, pp 947-948; doi:10.1038/s41591-021-01350-5

Abstract:
One Health approaches recognize the links between the environment, animals, and human disease, but these approaches are successful only with bottom-up community engagement, education, and international collaborations.
Akaninyene Otu, Emmanuel Effa, , Simeon Cadmus, Chinwe Ochu, Rauna Athingo, Eve Namisango, Dimie Ogoina, Friday Okonofua, Bassey Ebenso
Published: 20 May 2021
Nature Medicine, Volume 27, pp 943-946; doi:10.1038/s41591-021-01375-w

Abstract:
Urbanization, armed conflict, and deforestation in African countries have increased the risk of zoonotic infections, which requires a One Health approach focused on the environment, animal health and human health.
Karen O’Leary
Published: 20 May 2021
by 10.1038
Nature Medicine; doi:10.1038/d41591-021-00034-4

The publisher has not yet granted permission to display this abstract.
Guowei Li, Wanmin Lian, Hongying Qu, Ziyi Li, Qiru Zhou, Junzhang Tian
Published: 20 May 2021
Nature Medicine, Volume 27, pp 936-937; doi:10.1038/s41591-021-01376-9

, Eyal David, Pierluigi Ramadori, Dominik Pfister, Michael Safran, Baoguo At The, Amir Giladi, Diego Adhemar Jaitin, Oren Barboy, Merav Cohen, et al.
Published: 20 May 2021
Nature Medicine, Volume 27, pp 1043-1054; doi:10.1038/s41591-021-01344-3

Abstract:
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology. Single-cell analyses reveal cDC1 as conserved immunological drivers of non-alcoholic steatohepatitis in mice and humans
, Jennifer E. Miller, Nilay D. Shah,
Published: 20 May 2021
Nature Medicine, Volume 27, pp 940-943; doi:10.1038/s41591-021-01368-9

Abstract:
Increasingly, data are collected by companies that provide direct-to-consumer personal genomic tests, yet the existing health legislation covering the use of these data is lagging far behind in the USA.
Erin M. Bange, Nicholas A. Han, Paul Wileyto, Justin Y. Kim, , James Robinson, Allison R. Greenplate, Madeline A. Hwee, Florence Porterfield, Olutosin Owoyemi, et al.
Published: 20 May 2021
Nature Medicine, Volume 27, pp 1-10; doi:10.1038/s41591-021-01386-7

Abstract:
Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses. A study of hospitalized patients infected with SARS-CoV-2 and who have liquid or solid cancer suggests that hematologic malignancy is an independent risk factor for mortality and that CD8+ T cells might limit infection in this setting irrespective of humoral immunity.
, Rebecca Weintraub, Michelle A. Williams, Kate Miller, Alison Buttenheim, Emily Sadecki, Helen Wu, Aditi Doiphode, Neha Nagpal, Lawrence O. Gostin, et al.
Published: 18 May 2021
Nature Medicine, Volume 27, pp 1298-1307; doi:10.1038/s41591-021-01379-6

Abstract:
Many vaccine rationing guidelines urge planners to recognize, and ideally reduce, inequities. In the United States, allocation frameworks are determined by each of the Centers for Disease Control and Prevention’s 64 jurisdictions (50 states, the District of Columbia, five cities and eight territories). In this study, we analyzed vaccine allocation plans published by 8 November 2020, tracking updates through to 30 March 2021. We evaluated whether jurisdictions adopted proposals to reduce inequity using disadvantage indices and related place-based measures. By 30 March 2021, 14 jurisdictions had prioritized specific zip codes in combination with metrics such as COVID-19 incidence, and 37 jurisdictions (including 34 states) had adopted disadvantage indices, compared to 19 jurisdictions in November 2020. Uptake of indices doubled from 7 to 14 among the jurisdictions with the largest shares of disadvantaged communities. Five applications were distinguished: (1) prioritizing disadvantaged groups through increased shares of vaccines or vaccination appointments; (2) defining priority groups or areas; (3) tailoring outreach and communication; (4) planning the location of dispensing sites; and (5) monitoring receipt. To ensure that equity features centrally in allocation plans, policymakers at the federal, state and local levels should universalize the uptake of disadvantage indices and related place-based measures. An analysis of COVID-19 vaccine allocation frameworks in the United States across 64 Centers for Disease Control and Prevention jurisdictions reveals that, as of 31 March 2021, 37 jurisdictions had adopted disadvantage indices to reduce health disparities. The analysis also highlights the importance of vaccine prioritization based on health and place.
, Philipe Gobeil, Annie Séguin, Judith Atkins, Iohann Boulay, Pierre-Yves Charbonneau, Manon Couture, Marc-André D’Aoust, Jiwanjeet Dhaliwall, Carolyn Finkle, et al.
Published: 18 May 2021
Nature Medicine, Volume 27, pp 1071-1078; doi:10.1038/s41591-021-01370-1

Abstract:
Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18–55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 μg, 7.5 μg, and 15 μg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.
Published: 17 May 2021
Nature Medicine, Volume 27, pp 1205-1211; doi:10.1038/s41591-021-01377-8

Abstract:
Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic. Estimates of the levels of neutralizing antibodies necessary for protection against symptomatic SARS-CoV-2 or severe COVID-19 are a fraction of the mean level in convalescent serum and will be useful in guiding vaccine rollouts.
, , Salma M. Abdalla, Anne-Sophie Jung, Melisa Tan, Shishi Wu, Alvin Chua, Monica Verma, Pami Shrestha, Sudhvir Singh, et al.
Published: 17 May 2021
Nature Medicine, Volume 27, pp 964-980; doi:10.1038/s41591-021-01381-y

Abstract:
Health systems resilience is key to learning lessons from country responses to crises such as coronavirus disease 2019 (COVID-19). In this perspective, we review COVID-19 responses in 28 countries using a new health systems resilience framework. Through a combination of literature review, national government submissions and interviews with experts, we conducted a comparative analysis of national responses. We report on domains addressing governance and financing, health workforce, medical products and technologies, public health functions, health service delivery and community engagement to prevent and mitigate the spread of COVID-19. We then synthesize four salient elements that underlie highly effective national responses and offer recommendations toward strengthening health systems resilience globally. A review of COVID-19 responses in 28 selected countries identifies elements of highly effective public health responses and offers recommendations toward strengthening health systems resilience.
Published: 14 May 2021
Nature Medicine, Volume 27, pp 737-737; doi:10.1038/s41591-021-01373-y

Abstract:
Enhancing population diversity in genetic databases and evaluating genetic scores in conjunction with other disease factors will be needed to ensure a more equitable impact of precision medicine.
, , Francesco Ciompi
Published: 14 May 2021
Nature Medicine, Volume 27, pp 775-784; doi:10.1038/s41591-021-01343-4

Abstract:
Machine learning techniques have great potential to improve medical diagnostics, offering ways to improve accuracy, reproducibility and speed, and to ease workloads for clinicians. In the field of histopathology, deep learning algorithms have been developed that perform similarly to trained pathologists for tasks such as tumor detection and grading. However, despite these promising results, very few algorithms have reached clinical implementation, challenging the balance between hope and hype for these new techniques. This Review provides an overview of the current state of the field, as well as describing the challenges that still need to be addressed before artificial intelligence in histopathology can achieve clinical value. Recent advances in machine learning techniques have created opportunities to improve medical diagnostics, but implementing these advances in the clinic will not be without challenge.
, Lara Curran, Yili Zhao, Jami C. Levine, Erin Chinn, Anita J. Moon-Grady
Published: 14 May 2021
Nature Medicine, Volume 27, pp 882-891; doi:10.1038/s41591-021-01342-5

Abstract:
Congenital heart disease (CHD) is the most common birth defect. Fetal screening ultrasound provides five views of the heart that together can detect 90% of complex CHD, but in practice, sensitivity is as low as 30%. Here, using 107,823 images from 1,326 retrospective echocardiograms and screening ultrasounds from 18- to 24-week fetuses, we trained an ensemble of neural networks to identify recommended cardiac views and distinguish between normal hearts and complex CHD. We also used segmentation models to calculate standard fetal cardiothoracic measurements. In an internal test set of 4,108 fetal surveys (0.9% CHD, >4.4 million images), the model achieved an area under the curve (AUC) of 0.99, 95% sensitivity (95% confidence interval (CI), 84–99%), 96% specificity (95% CI, 95–97%) and 100% negative predictive value in distinguishing normal from abnormal hearts. Model sensitivity was comparable to that of clinicians and remained robust on outside-hospital and lower-quality images. The model’s decisions were based on clinically relevant features. Cardiac measurements correlated with reported measures for normal and abnormal hearts. Applied to guideline-recommended imaging, ensemble learning models could significantly improve detection of fetal CHD, a critical and global diagnostic challenge. Deep learning can facilitate identification of congenital heart disease from fetal ultrasound screening, a diagnosis that in clinical practice is often missed.
, Keila N. Lopez
Published: 14 May 2021
Nature Medicine, Volume 27, pp 764-765; doi:10.1038/s41591-021-01354-1

Abstract:
New advances in machine learning could facilitate and reduce disparities in the prenatal diagnosis of congenital health disease, the most common and lethal birth defect.
Karen O’Leary
Published: 13 May 2021
Nature Medicine; doi:10.1038/d41591-021-00031-7

Abstract:
The RECOVERY study shows that anti-IL-6 agent tocilizumab improves outcomes in hypoxic patients with COVID-19. The RECOVERY study shows that anti-IL-6 agent tocilizumab improves outcomes in hypoxic patients with COVID-19.
Karen O’Leary
Published: 13 May 2021
Nature Medicine; doi:10.1038/d41591-021-00032-6

Abstract:
Stimulants and α2-adrenergic agonists both improve symptoms of ADHD in preschool-age children, but they have different side effects. Stimulants and α2-adrenergic agonists both improve symptoms of ADHD in preschool-age children, but they have different side effects.
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