Journal: Nat Med

Sorted by: date / impact
Abstract

Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota.

Vogl T, Klompus S, Leviatan S, Kalka IN, ... Weersma RK, Segal E
Serum antibodies can recognize both pathogens and commensal gut microbiota. However, our current understanding of antibody repertoires is largely based on DNA sequencing of the corresponding B-cell receptor genes, and actual bacterial antigen targets remain incompletely characterized. Here we have profiled the serum antibody responses of 997 healthy individuals against 244,000 rationally selected peptide antigens derived from gut microbiota and pathogenic and probiotic bacteria. Leveraging phage immunoprecipitation sequencing (PhIP-Seq) based on phage-displayed synthetic oligo libraries, we detect a wide breadth of individual-specific as well as shared antibody responses against microbiota that associate with age and gender. We also demonstrate that these antibody epitope repertoires are more longitudinally stable than gut microbiome species abundances. Serum samples of more than 200 individuals collected five years apart could be accurately matched and could serve as an immunologic fingerprint. Overall, our results suggest that systemic antibody responses provide a non-redundant layer of information about microbiota beyond gut microbial species composition.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 18 Jul 2021; epub ahead of print
Vogl T, Klompus S, Leviatan S, Kalka IN, ... Weersma RK, Segal E
Nat Med: 18 Jul 2021; epub ahead of print | PMID: 34282338
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Abstract

COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries.

Solís Arce JS, Warren SS, Meriggi NF, Scacco A, ... Mobarak AM, Omer SB
Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs.

© 2021. The Author(s).

Nat Med: 15 Jul 2021; epub ahead of print
Solís Arce JS, Warren SS, Meriggi NF, Scacco A, ... Mobarak AM, Omer SB
Nat Med: 15 Jul 2021; epub ahead of print | PMID: 34272499
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Abstract

Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination.

Barros-Martins J, Hammerschmidt SI, Cossmann A, Odak I, ... Förster R, Behrens GMN
Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca\'s ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School\'s COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer\'s BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.

© 2021. The Author(s).

Nat Med: 13 Jul 2021; epub ahead of print
Barros-Martins J, Hammerschmidt SI, Cossmann A, Odak I, ... Förster R, Behrens GMN
Nat Med: 13 Jul 2021; epub ahead of print | PMID: 34262158
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Abstract

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis.

Vitanza NA, Johnson AJ, Wilson AL, Brown C, ... Jensen MC, Park JR
Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children\'s evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 11 Jul 2021; epub ahead of print
Vitanza NA, Johnson AJ, Wilson AL, Brown C, ... Jensen MC, Park JR
Nat Med: 11 Jul 2021; epub ahead of print | PMID: 34253928
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Abstract

A human three-dimensional neural-perivascular \'assembloid\' promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology.

Wang L, Sievert D, Clark AE, Lee S, ... Carlin AF, Gleeson JG
Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral \'replication hubs\', with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new \'assembloid\' model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 08 Jul 2021; epub ahead of print
Wang L, Sievert D, Clark AE, Lee S, ... Carlin AF, Gleeson JG
Nat Med: 08 Jul 2021; epub ahead of print | PMID: 34244682
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Abstract

mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.

Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, ... Bertollini R, Abu-Raddad LJ
The SARS-CoV-2 pandemic continues to be a global health concern. The mRNA-1273 (Moderna) vaccine was reported to have an efficacy of 94.1% at preventing symptomatic COVID-19 due to infection with \'wild-type\' variants in a randomized clinical trial. Here, we assess the real-world effectiveness of this vaccine against SARS-CoV-2 variants of concern, specifically B.1.1.7 (Alpha) and B.1.351 (Beta), in Qatar, a population that comprises mainly working-age adults, using a matched test-negative, case-control study design. We show that vaccine effectiveness was negligible for 2 weeks after the first dose, but increased rapidly in the third and fourth weeks immediately before administration of a second dose. Effectiveness against B.1.1.7 infection was 88.1% (95% confidence interval (CI): 83.7-91.5%) ≥14 days after the first dose but before the second dose, and was 100% (95% CI: 91.8-100.0%) ≥14 days after the second dose. Analogous effectiveness against B.1.351 infection was 61.3% after the first dose (95% CI: 56.5-65.5%) and 96.4% after the second dose (95% CI: 91.9-98.7%). Effectiveness against any severe, critical or fatal COVID-19 disease due to any SARS-CoV-2 infection (predominantly B.1.1.7 and B.1.351) was 81.6% (95% CI: 71.0-88.8%) and 95.7% (95% CI: 73.4-99.9%) after the first and second dose, respectively. The mRNA-1273 vaccine is highly effective against B.1.1.7 and B.1.351 infections, whether symptomatic or asymptomatic, and against any COVID-19 hospitalization and death, even after a single dose.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 08 Jul 2021; epub ahead of print
Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, ... Bertollini R, Abu-Raddad LJ
Nat Med: 08 Jul 2021; epub ahead of print | PMID: 34244681
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Abstract

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, ... Zitvogel L, Wargo JA
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.



Nat Med: 07 Jul 2021; epub ahead of print
Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, ... Zitvogel L, Wargo JA
Nat Med: 07 Jul 2021; epub ahead of print | PMID: 34239137
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Abstract

Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.

Dedrick RM, Freeman KG, Nguyen JA, Bahadirli-Talbott A, ... Hatfull GF, Cohen KA
An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for 6 months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load tenfold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM- and IgG-mediated neutralizing antibody response to the phages, which was associated with limited therapeutic efficacy.



Nat Med: 07 Jul 2021; epub ahead of print
Dedrick RM, Freeman KG, Nguyen JA, Bahadirli-Talbott A, ... Hatfull GF, Cohen KA
Nat Med: 07 Jul 2021; epub ahead of print | PMID: 34239133
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Abstract

Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis.

Gygli SM, Loiseau C, Jugheli L, Adamia N, ... Avaliani Z, Gagneux S
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.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1171-1177
Gygli SM, Loiseau C, Jugheli L, Adamia N, ... Avaliani Z, Gagneux S
Nat Med: 29 Jun 2021; 27:1171-1177 | PMID: 34031604
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Abstract

Partial recovery of visual function in a blind patient after optogenetic therapy.

Sahel JA, Boulanger-Scemama E, Pagot C, Arleo A, ... Taiel M, Roska B
Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1223-1229
Sahel JA, Boulanger-Scemama E, Pagot C, Arleo A, ... Taiel M, Roska B
Nat Med: 29 Jun 2021; 27:1223-1229 | PMID: 34031601
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Abstract

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

Mohassel P, Donkervoort S, Lone MA, Nalls M, ... Dunn TM, Bönnemann CG
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.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 29 Jun 2021; 27:1197-1204
Mohassel P, Donkervoort S, Lone MA, Nalls M, ... Dunn TM, Bönnemann CG
Nat Med: 29 Jun 2021; 27:1197-1204 | PMID: 34059824
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Abstract

Deep learning of HIV field-based rapid tests.

Turbé V, Herbst C, Mngomezulu T, Meshkinfamfard S, ... Shahmanesh M, McKendry RA
Although deep learning algorithms show increasing promise for disease diagnosis, their use with rapid diagnostic tests performed in the field has not been extensively tested. Here we use deep learning to classify images of rapid human immunodeficiency virus (HIV) tests acquired in rural South Africa. Using newly developed image capture protocols with the Samsung SM-P585 tablet, 60 fieldworkers routinely collected images of HIV lateral flow tests. From a library of 11,374 images, deep learning algorithms were trained to classify tests as positive or negative. A pilot field study of the algorithms deployed as a mobile application demonstrated high levels of sensitivity (97.8%) and specificity (100%) compared with traditional visual interpretation by humans-experienced nurses and newly trained community health worker staff-and reduced the number of false positives and false negatives. Our findings lay the foundations for a new paradigm of deep learning-enabled diagnostics in low- and middle-income countries, termed REASSURED diagnostics1, an acronym for real-time connectivity, ease of specimen collection, affordable, sensitive, specific, user-friendly, rapid, equipment-free and deliverable. Such diagnostics have the potential to provide a platform for workforce training, quality assurance, decision support and mobile connectivity to inform disease control strategies, strengthen healthcare system efficiency and improve patient outcomes and outbreak management in emerging infections.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1165-1170
Turbé V, Herbst C, Mngomezulu T, Meshkinfamfard S, ... Shahmanesh M, McKendry RA
Nat Med: 29 Jun 2021; 27:1165-1170 | PMID: 34140702
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Abstract

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer\'s disease.

Salloway S, Farlow M, McDade E, Clifford DB, ... Bateman RJ, Dominantly Inherited Alzheimer Network–Trials Unit
Dominantly inherited Alzheimer\'s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1187-1196
Salloway S, Farlow M, McDade E, Clifford DB, ... Bateman RJ, Dominantly Inherited Alzheimer Network–Trials Unit
Nat Med: 29 Jun 2021; 27:1187-1196 | PMID: 34155411
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Abstract

Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease.

Scott BM, Gutiérrez-Vázquez C, Sanmarco LM, da Silva Pereira JA, ... Peisajovich SG, Quintana FJ
Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1212-1222
Scott BM, Gutiérrez-Vázquez C, Sanmarco LM, da Silva Pereira JA, ... Peisajovich SG, Quintana FJ
Nat Med: 29 Jun 2021; 27:1212-1222 | PMID: 34183837
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Abstract

Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial.

Mocanu V, Zhang Z, Deehan EC, Kao DH, ... Walter J, Madsen KL
Fecal microbial transplantation (FMT) from lean donors to patients with obesity has been associated with metabolic benefits, yet results so far have been inconsistent. In this study, we tested the application of daily fiber supplementation as an adjunct to FMT therapy to modulate cardiometabolic outcomes. We performed a double-blind randomized trial in patients with severe obesity and metabolic syndrome receiving oral FMT, to test high-fermentable (HF) and low-fermentable (LF) fiber supplements (NCT03477916). Seventy participants were randomized to the FMT-HF (n = 17), FMT-LF (n = 17), HF (n = 17) and LF (n = 19) groups. The primary outcome was the assessment of change in insulin sensitivity from baseline to 6 weeks using the homeostatic model assessment (HOMA2-IR/IS). After 6 weeks, only patients in the FMT-LF group had significant improvements in HOMA2-IR (3.16 ± 3.01 at 6 weeks versus 3.77 ± 3.57 at baseline; P = 0.02). No difference in HOMA2-IR was observed over this period for those in the FMT-HF group (3.25 ± 1.70 at 6 weeks versus 3.17 ± 1.72 at baseline; P = 0.8), the HF group (3.49 ± 1.43 at 6 weeks versus 3.26 ± 1.33 at baseline; P = 0.8) or the LF group (3.76 ± 2.01 at 6 weeks versus 3.56 ± 1.81 at baseline; P = 0.8). Interventions were safe and well-tolerated with no treatment-attributed serious adverse events. We provide proof of concept for the use of a single-dose oral FMT combined with daily low-fermentable fiber supplementation to improve insulin sensitivity in patients with severe obesity and metabolic syndrome.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1272-1279
Mocanu V, Zhang Z, Deehan EC, Kao DH, ... Walter J, Madsen KL
Nat Med: 29 Jun 2021; 27:1272-1279 | PMID: 34226737
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Abstract

Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.

Harrison SA, Ruane PJ, Freilich BL, Neff G, ... Cheng A, Yale K
Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1-2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1-2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1-F3 stage NASH, with an acceptable safety profile.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1262-1271
Harrison SA, Ruane PJ, Freilich BL, Neff G, ... Cheng A, Yale K
Nat Med: 29 Jun 2021; 27:1262-1271 | PMID: 34239138
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Abstract

Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis.

Saiki R, Momozawa Y, Nannya Y, Nakagawa MM, ... Makishima H, Ogawa S
Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1239-1249
Saiki R, Momozawa Y, Nannya Y, Nakagawa MM, ... Makishima H, Ogawa S
Nat Med: 29 Jun 2021; 27:1239-1249 | PMID: 34239136
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Abstract

An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer.

Voabil P, de Bruijn M, Roelofsen LM, Hendriks SH, ... Schumacher TN, Thommen DS
Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Jun 2021; 27:1250-1261
Voabil P, de Bruijn M, Roelofsen LM, Hendriks SH, ... Schumacher TN, Thommen DS
Nat Med: 29 Jun 2021; 27:1250-1261 | PMID: 34239134
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Abstract

100 years of insulin: celebrating the past, present and future of diabetes therapy.

Sims EK, Carr ALJ, Oram RA, DiMeglio LA, Evans-Molina C
The year 2021 marks the centennial of Banting and Best\'s landmark description of the discovery of insulin. This discovery and insulin\'s rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 29 Jun 2021; 27:1154-1164
Sims EK, Carr ALJ, Oram RA, DiMeglio LA, Evans-Molina C
Nat Med: 29 Jun 2021; 27:1154-1164 | PMID: 34267380
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Abstract

Reduction in life expectancy in Brazil after COVID-19.

Castro MC, Gurzenda S, Turra CM, Kim S, Andrasfay T, Goldman N
Brazil has been heavily affected by coronavirus disease 2019 (COVID-19). In this study, we used data on reported total deaths in 2020 and in January-April 2021 to measure and compare the death toll across states. We estimate a decline in 2020 life expectancy at birth (e0) of 1.3 years, a mortality level not seen since 2014. The reduction in life expectancy at age 65 (e65) in 2020 was 0.9 years, setting Brazil back to 2012 levels. The decline was larger for males, widening by 9.1% the female-male gap in e0. Among states, Amazonas lost 60.4% of the improvements in e0 since 2000. In the first 4 months of 2021, COVID-19 deaths represented 107% of the total 2020 figures. Assuming that death rates would have been equal to 2019 all-cause rates in the absence of COVID-19, COVID-19 deaths in 2021 have already reduced e0 in 2021 by 1.8 years, which is slightly larger than the reduction estimated for 2020 under similar assumptions.



Nat Med: 28 Jun 2021; epub ahead of print
Castro MC, Gurzenda S, Turra CM, Kim S, Andrasfay T, Goldman N
Nat Med: 28 Jun 2021; epub ahead of print | PMID: 34188224
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Impact:
Abstract

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

Ogishi M, Yang R, Aytekin C, Langlais D, ... Boisson-Dupuis S, Casanova JL
The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient\'s leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient\'s lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.



Nat Med: 27 Jun 2021; epub ahead of print
Ogishi M, Yang R, Aytekin C, Langlais D, ... Boisson-Dupuis S, Casanova JL
Nat Med: 27 Jun 2021; epub ahead of print | PMID: 34183838
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Impact:
Abstract

Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection.

Salje H, Alera MT, Chua MN, Hunsawong T, ... Fernandez S, Rothman AL
More than half of the world\'s population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.



Nat Med: 23 Jun 2021; epub ahead of print
Salje H, Alera MT, Chua MN, Hunsawong T, ... Fernandez S, Rothman AL
Nat Med: 23 Jun 2021; epub ahead of print | PMID: 34168334
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Impact:
Abstract

Long COVID in a prospective cohort of home-isolated patients.

Blomberg B, Mohn KG, Brokstad KA, Zhou F, ... Cox RJ, Langeland N
Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients-247 home-isolated and 65 hospitalized-comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16-30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.



Nat Med: 22 Jun 2021; epub ahead of print
Blomberg B, Mohn KG, Brokstad KA, Zhou F, ... Cox RJ, Langeland N
Nat Med: 22 Jun 2021; epub ahead of print | PMID: 34163090
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Impact:
Abstract

Integrated genomic, epidemiologic investigation of Candida auris skin colonization in a skilled nursing facility.

Proctor DM, Dangana T, Sexton DJ, Fukuda C, ... Segre JA, Hayden MK
Candida auris is a fungal pathogen of high concern due to its ability to cause healthcare-associated infections and outbreaks, its resistance to antimicrobials and disinfectants and its persistence on human skin and in the inanimate environment. To inform surveillance and future mitigation strategies, we defined the extent of skin colonization and explored the microbiome associated with C. auris colonization. We collected swab specimens and clinical data at three times points between January and April 2019 from 57 residents (up to ten body sites each) of a ventilator-capable skilled nursing facility with endemic C. auris and routine chlorhexidine gluconate (CHG) bathing. Integrating microbial-genomic and epidemiologic data revealed occult C. auris colonization of multiple body sites not targeted commonly for screening. High concentrations of CHG were associated with suppression of C. auris growth but not with deleterious perturbation of commensal microbes. Modeling human mycobiome dynamics provided insight into underlying alterations to the skin fungal community as a possible modifiable risk factor for acquisition and persistence of C. auris. Failure to detect the extensive, disparate niches of C. auris colonization may reduce the effectiveness of infection-prevention measures that target colonized residents, highlighting the importance of universal strategies to reduce C. auris transmission.



Nat Med: 20 Jun 2021; epub ahead of print
Proctor DM, Dangana T, Sexton DJ, Fukuda C, ... Segre JA, Hayden MK
Nat Med: 20 Jun 2021; epub ahead of print | PMID: 34155414
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Impact:
Abstract

Retrieval of vector integration sites from cell-free DNA.

Cesana D, Calabria A, Rudilosso L, Gallina P, ... Naldini L, Montini E
Gene therapy (GT) has rapidly attracted renewed interest as a treatment for otherwise incurable diseases, with several GT products already on the market and many more entering clinical testing for selected indications. Clonal tracking techniques based on vector integration enable monitoring of the fate of engineered cells in the blood of patients receiving GT and allow assessment of the safety and efficacy of these procedures. However, owing to the limited number of cells that can be tested and the impracticality of studying cells residing in peripheral organs without performing invasive biopsies, this approach provides only a partial snapshot of the clonal repertoire and dynamics of genetically modified cells and reduces the predictive power as a safety readout. In this study, we developed liquid biopsy integration site sequencing, or LiBIS-seq, a polymerase chain reaction technique optimized to quantitatively retrieve vector integration sites from cell-free DNA released into the bloodstream by dying cells residing in several tissues. This approach enabled longitudinal monitoring of in vivo liver-directed GT and clonal tracking in patients receiving hematopoietic stem cell GT, improving our understanding of the clonal composition and turnover of genetically modified cells in solid tissues and, in contrast to conventional analyses based only on circulating blood cells, enabling earlier detection of vector-marked clones that are aberrantly expanding in peripheral tissues.



Nat Med: 16 Jun 2021; epub ahead of print
Cesana D, Calabria A, Rudilosso L, Gallina P, ... Naldini L, Montini E
Nat Med: 16 Jun 2021; epub ahead of print | PMID: 34140705
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Impact:
Abstract

Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals.

Kustin T, Harel N, Finkel U, Perchik S, ... Ben-Shachar S, Stern A
The BNT162b2 mRNA vaccine is highly effective against SARS-CoV-2. However, apprehension exists that variants of concern (VOCs) may evade vaccine protection, due to evidence of reduced neutralization of the VOCs B.1.1.7 and B.1.351 by vaccine sera in laboratory assays. We performed a matched cohort study to examine the distribution of VOCs in infections of BNT162b2 mRNA vaccinees from Clalit Health Services (Israel) using viral genomic sequencing, and hypothesized that if vaccine effectiveness against a VOC is reduced, its proportion among breakthrough cases would be higher than in unvaccinated controls. Analyzing 813 viral genome sequences from nasopharyngeal swabs, we showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7. These findings suggest reduced vaccine effectiveness against both VOCs within particular time windows. Our results emphasize the importance of rigorously tracking viral variants, and of increasing vaccination to prevent the spread of VOCs.



Nat Med: 13 Jun 2021; epub ahead of print
Kustin T, Harel N, Finkel U, Perchik S, ... Ben-Shachar S, Stern A
Nat Med: 13 Jun 2021; epub ahead of print | PMID: 34127854
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Impact:
Abstract

Community-level evidence for SARS-CoV-2 vaccine protection of unvaccinated individuals.

Milman O, Yelin I, Aharony N, Katz R, ... Patalon T, Kishony R
Mass vaccination has the potential to curb the current COVID-19 pandemic by protecting individuals who have been vaccinated against the disease and possibly lowering the likelihood of transmission to individuals who have not been vaccinated. The high effectiveness of the widely administered BNT162b vaccine from Pfizer-BioNTech in preventing not only the disease but also infection with SARS-CoV-2 suggests a potential for a population-level effect, which is critical for disease eradication. However, this putative effect is difficult to observe, especially in light of highly fluctuating spatiotemporal epidemic dynamics. Here, by analyzing vaccination records and test results collected during the rapid vaccine rollout in a large population from 177 geographically defined communities, we find that the rates of vaccination in each community are associated with a substantial later decline in infections among a cohort of individuals aged under 16 years, who are unvaccinated. On average, for each 20 percentage points of individuals who are vaccinated in a given population, the positive test fraction for the unvaccinated population decreased approximately twofold. These results provide observational evidence that vaccination not only protects individuals who have been vaccinated but also provides cross-protection to unvaccinated individuals in the community.



Nat Med: 09 Jun 2021; epub ahead of print
Milman O, Yelin I, Aharony N, Katz R, ... Patalon T, Kishony R
Nat Med: 09 Jun 2021; epub ahead of print | PMID: 34113015
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Impact:
Abstract

Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom.

Pritchard E, Matthews PC, Stoesser N, Eyre DW, ... Walker AS, Pouwels KB
The effectiveness of COVID-19 vaccination in preventing new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general community is still unclear. Here, we used the Office for National Statistics COVID-19 Infection Survey-a large community-based survey of individuals living in randomly selected private households across the United Kingdom-to assess the effectiveness of the BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30; as a surrogate for viral load) and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 real-time PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 d after the first dose (61% (95% confidence interval (CI) = 54-68%) versus 66% (95% CI = 60-71%), respectively), with greater reductions observed after a second dose (79% (95% CI = 65-88%) versus 80% (95% CI = 73-85%), respectively). The largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of a difference between the BNT162b2 and ChAdOx1 vaccines.



Nat Med: 08 Jun 2021; epub ahead of print
Pritchard E, Matthews PC, Stoesser N, Eyre DW, ... Walker AS, Pouwels KB
Nat Med: 08 Jun 2021; epub ahead of print | PMID: 34108716
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Impact:
Abstract

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Liu D, Lin JR, Robitschek EJ, Kasumova GG, ... Sorger PK, Boland GM
Despite initial responses1-3, most melanoma patients develop resistance4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFRhi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.



Nat Med: 30 May 2021; 27:985-992
Liu D, Lin JR, Robitschek EJ, Kasumova GG, ... Sorger PK, Boland GM
Nat Med: 30 May 2021; 27:985-992 | PMID: 33941922
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Impact:
Abstract

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, ... Emerson A, Doblin R
Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.



Nat Med: 30 May 2021; 27:1025-1033
Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, ... Emerson A, Doblin R
Nat Med: 30 May 2021; 27:1025-1033 | PMID: 33972795
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Impact:
Abstract

XCR1 type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.

Deczkowska A, David E, Ramadori P, Pfister D, ... Elinav E, Amit I
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.



Nat Med: 30 May 2021; 27:1043-1054
Deczkowska A, David E, Ramadori P, Pfister D, ... Elinav E, Amit I
Nat Med: 30 May 2021; 27:1043-1054 | PMID: 34017133
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Impact:
Abstract

Wearable sensors enable personalized predictions of clinical laboratory measurements.

Dunn J, Kidzinski L, Runge R, Witt D, ... Hastie T, Snyder MP
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.



Nat Med: 30 May 2021; 27:1105-1112
Dunn J, Kidzinski L, Runge R, Witt D, ... Hastie T, Snyder MP
Nat Med: 30 May 2021; 27:1105-1112 | PMID: 34031607
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Impact:
Abstract

Prediction of future Alzheimer\'s disease dementia using plasma phospho-tau combined with other accessible measures.

Palmqvist S, Tideman P, Cullen N, Zetterberg H, ... Mattsson-Carlgren N, Hansson O
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.



Nat Med: 30 May 2021; 27:1034-1042
Palmqvist S, Tideman P, Cullen N, Zetterberg H, ... Mattsson-Carlgren N, Hansson O
Nat Med: 30 May 2021; 27:1034-1042 | PMID: 34031605
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Impact:
Abstract

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.

Wade KH, Lam BYH, Melvin A, Pan W, ... Timpson NJ, O\'Rahilly S
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.



Nat Med: 30 May 2021; 27:1088-1096
Wade KH, Lam BYH, Melvin A, Pan W, ... Timpson NJ, O'Rahilly S
Nat Med: 30 May 2021; 27:1088-1096 | PMID: 34045736
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Impact:
Abstract

Biomarkers for neurodegenerative diseases.

Hansson O
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.



Nat Med: 30 May 2021; 27:954-963
Hansson O
Nat Med: 30 May 2021; 27:954-963 | PMID: 34083813
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Impact:
Abstract

Clinical integration of machine learning for curative-intent radiation treatment of patients with prostate cancer.

McIntosh C, Conroy L, Tjong MC, Craig T, ... Berlin A, Purdie TG
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.



Nat Med: 30 May 2021; 27:999-1005
McIntosh C, Conroy L, Tjong MC, Craig T, ... Berlin A, Purdie TG
Nat Med: 30 May 2021; 27:999-1005 | PMID: 34083812
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Impact:
Abstract

Phenotypic signatures in clinical data enable systematic identification of patients for genetic testing.

Morley TJ, Han L, Castro VM, Morra J, ... Bastarache L, Ruderfer DM
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.



Nat Med: 30 May 2021; 27:1097-1104
Morley TJ, Han L, Castro VM, Morra J, ... Bastarache L, Ruderfer DM
Nat Med: 30 May 2021; 27:1097-1104 | PMID: 34083811
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Impact:
Abstract

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Zekavat SM, Lin SH, Bick AG, Liu A, ... Genovese G, Natarajan P
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.



Nat Med: 30 May 2021; 27:1012-1024
Zekavat SM, Lin SH, Bick AG, Liu A, ... Genovese G, Natarajan P
Nat Med: 30 May 2021; 27:1012-1024 | PMID: 34099924
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Impact:
Abstract

HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults.

Dharan NJ, Yeh P, Bloch M, Yeung MM, ... Dawson MA, ARCHIVE Study Group
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.



Nat Med: 30 May 2021; 27:1006-1011
Dharan NJ, Yeh P, Bloch M, Yeung MM, ... Dawson MA, ARCHIVE Study Group
Nat Med: 30 May 2021; 27:1006-1011 | PMID: 34099923
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Abstract

Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial.

Saxena AR, Gorman DN, Esquejo RM, Bergman A, ... Griffith DA, Kim AM
Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.



Nat Med: 30 May 2021; 27:1079-1087
Saxena AR, Gorman DN, Esquejo RM, Bergman A, ... Griffith DA, Kim AM
Nat Med: 30 May 2021; 27:1079-1087 | PMID: 34127852
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Abstract

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

Au L, Fendler A, Shepherd STC, Rzeniewicz K, ... CAPTURE Consortium, Turajlic S
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.



Nat Med: 25 May 2021; epub ahead of print
Au L, Fendler A, Shepherd STC, Rzeniewicz K, ... CAPTURE Consortium, Turajlic S
Nat Med: 25 May 2021; epub ahead of print | PMID: 34040262
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This program is still in alpha version.