Journal: Nat Med

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Abstract

A multisystem, cardio-renal investigation of post-COVID-19 illness.

Morrow AJ, Sykes R, McIntosh A, Kamdar A, ... Mangion K, Berry C
The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607 ). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28-60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28-60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was \'very likely\' in 21 (13%) patients, \'probable\' in 65 (41%) patients, \'unlikely\' in 56 (35%) patients and \'not present\' in 17 (11%) patients. At 28-60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

© 2022. The Author(s).

Nat Med: 23 May 2022; epub ahead of print
Morrow AJ, Sykes R, McIntosh A, Kamdar A, ... Mangion K, Berry C
Nat Med: 23 May 2022; epub ahead of print | PMID: 35606551
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Abstract

Effectiveness of CoronaVac in children 3 to 5 years during the SARS-CoV-2 Omicron outbreak in Chile.

Jara A, Undurraga EA, Zubizarreta JR, González C, ... García-Escorza H, Araos R
The outbreak of the B.1.1.529 lineage of SARS-CoV-2 (Omicron) has caused an unprecedented number of COVID-19 cases, including pediatric hospital admissions. Policymakers urgently need evidence of vaccine effectiveness in children to balance the costs and benefits of vaccination campaigns, but to date, the evidence is sparse. Leveraging a population-based cohort in Chile of 490,694 children aged 3-5 years, we estimated the effectiveness of administering a two-dose schedule, 28 days apart, of Sinovac\'s inactivated SARS-CoV-2 vaccine (CoronaVac). We used inverse probability-weighted survival regression models to estimate hazard ratios of symptomatic COVID-19, hospitalization, and admission to an intensive care unit (ICU) for children with complete immunization over non-vaccination, accounting for time-varying vaccination exposure and relevant confounders. The study was conducted between December 6, 2021, and February 26, 2022, during the Omicron outbreak in Chile. The estimated vaccine effectiveness was 38.2% (95% confidence intervals, CI, 36.5-39.9) against symptomatic COVID-19, 64.6% (95%CI, 49.6-75.2) against hospitalization, and 69.0% (95%CI, 18.6-88.2) against ICU admission. The effectiveness against symptomatic COVID-19 was modest. However, protection against severe disease was high. These results support vaccination of children 3-5 years to prevent severe illness and associated complications and highlight the importance of maintaining layered protections against SARS-CoV-2 infection.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 23 May 2022; epub ahead of print
Jara A, Undurraga EA, Zubizarreta JR, González C, ... García-Escorza H, Araos R
Nat Med: 23 May 2022; epub ahead of print | PMID: 35605637
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Abstract

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial.

Rivellese F, Surace AEA, Goldmann K, Sciacca E, ... Pitzalis C, R4RA collaborative group
Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

© 2022. Crown.

Nat Med: 19 May 2022; epub ahead of print
Rivellese F, Surace AEA, Goldmann K, Sciacca E, ... Pitzalis C, R4RA collaborative group
Nat Med: 19 May 2022; epub ahead of print | PMID: 35589854
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Abstract

Machine learning model to predict mental health crises from electronic health records.

Garriga R, Mas J, Abraha S, Nolan J, ... Tadros G, Matic A
The timely identification of patients who are at risk of a mental health crisis can lead to improved outcomes and to the mitigation of burdens and costs. However, the high prevalence of mental health problems means that the manual review of complex patient records to make proactive care decisions is not feasible in practice. Therefore, we developed a machine learning model that uses electronic health records to continuously monitor patients for risk of a mental health crisis over a period of 28 days. The model achieves an area under the receiver operating characteristic curve of 0.797 and an area under the precision-recall curve of 0.159, predicting crises with a sensitivity of 58% at a specificity of 85%. A follow-up 6-month prospective study evaluated our algorithm\'s use in clinical practice and observed predictions to be clinically valuable in terms of either managing caseloads or mitigating the risk of crisis in 64% of cases. To our knowledge, this study is the first to continuously predict the risk of a wide range of mental health crises and to explore the added value of such predictions in clinical practice.

© 2022. The Author(s).

Nat Med: 16 May 2022; epub ahead of print
Garriga R, Mas J, Abraha S, Nolan J, ... Tadros G, Matic A
Nat Med: 16 May 2022; epub ahead of print | PMID: 35577964
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Abstract

Electronic cigarettes versus nicotine patches for smoking cessation in pregnancy: a randomized controlled trial.

Hajek P, Przulj D, Pesola F, Griffiths C, ... Manyonda I, Myers Smith K
Nicotine replacement therapy, in the form of nicotine patches, is commonly offered to pregnant women who smoke to help them to stop smoking, but this approach has limited efficacy in this population. Electronic cigarettes (e-cigarettes) are also used by pregnant women who smoke but their safety and efficacy in pregnancy are unknown. Here, we report the results of a randomized controlled trial in 1,140 participants comparing refillable e-cigarettes with nicotine patches. Pregnant women who smoked were randomized to e-cigarettes (n = 569) or nicotine patches (n = 571). In the unadjusted analysis of the primary outcome, validated prolonged quit rates at the end of pregnancy in the two study arms were not significantly different (6.8% versus 4.4% in the e-cigarette and patch arms, respectively; relative risk (RR) = 1.55, 95%CI: 0.95-2.53, P = 0.08). However, some participants in the nicotine patch group also used e-cigarettes during the study. In a pre-specified sensitivity analysis excluding abstinent participants who used non-allocated products, e-cigarettes were more effective than patches (6.8% versus 3.6%; RR = 1.93, 95%CI: 1.14-3.26, P = 0.02). Safety outcomes included adverse events and maternal and birth outcomes. The safety profile was found to be similar for both study products, however, low birthweight (<2,500 g) was less frequent in the e-cigarette arm (14.8% versus 9.6%; RR = 0.65, 95%CI: 0.47-0.90, P = 0.01). Other adverse events and birth outcomes were similar in the two study arms. E-cigarettes might help women who are pregnant to stop smoking, and their safety for use in pregnancy is similar to that of nicotine patches. ISRCTN62025374.

© 2022. The Author(s).

Nat Med: 16 May 2022; epub ahead of print
Hajek P, Przulj D, Pesola F, Griffiths C, ... Manyonda I, Myers Smith K
Nat Med: 16 May 2022; epub ahead of print | PMID: 35577966
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Abstract

Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial.

Haidar A, Lovblom LE, Cardinez N, Gouchie-Provencher N, ... Yale JF, Perkins BA
There is a need to optimize closed-loop automated insulin delivery in type 1 diabetes. We assessed the glycemic efficacy and safety of empagliflozin 25 mg d-1 as add-on therapy to insulin delivery with a closed-loop system. We performed a 2 × 2 factorial randomized, placebo-controlled, crossover two-center trial in adults, assessing 4 weeks of closed-loop delivery versus sensor-augmented pump (SAP) therapy and empagliflozin versus placebo. The primary outcome was time spent in the glucose target range (3.9-10.0 mmol l-1). Primary comparisons were empagliflozin versus placebo in each of closed-loop or SAP therapy; the remaining comparisons were conditional on its significance. Twenty-four of 27 randomized participants were included in the final analysis. Compared to placebo, empagliflozin improved time in target range with closed-loop therapy by 7.2% and in SAP therapy by 11.4%. Closed-loop therapy plus empagliflozin improved time in target range compared to SAP therapy plus empagliflozin by 6.1% but by 17.5% for the combination of closed-loop therapy and empagliflozin compared to SAP therapy plus placebo. While no diabetic ketoacidosis or severe hypoglycemia occurred during any intervention, uncomplicated ketosis events were more common on empagliflozin. Empagliflozin 25 mg d-1 added to automated insulin delivery improves glycemic control but increases ketone concentration and ketosis compared to placebo.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 12 May 2022; epub ahead of print
Haidar A, Lovblom LE, Cardinez N, Gouchie-Provencher N, ... Yale JF, Perkins BA
Nat Med: 12 May 2022; epub ahead of print | PMID: 35551290
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Abstract

Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.

Julg B, Stephenson KE, Wagh K, Tan SC, ... Korber B, Barouch DH
HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

© 2022. The Author(s).

Nat Med: 12 May 2022; epub ahead of print
Julg B, Stephenson KE, Wagh K, Tan SC, ... Korber B, Barouch DH
Nat Med: 12 May 2022; epub ahead of print | PMID: 35551291
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Abstract

Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.

Yang W, Zhu D, Gan S, Dong X, ... Li X, Chen L
Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 ).

© 2022. The Author(s).

Nat Med: 12 May 2022; epub ahead of print
Yang W, Zhu D, Gan S, Dong X, ... Li X, Chen L
Nat Med: 12 May 2022; epub ahead of print | PMID: 35551292
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Abstract

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.

Zhu D, Li X, Ma J, Zeng J, ... Yang W, Chen L
Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was -1.07% (-1.19%, -0.95%) in the dorzagliatin group and -0.50% (-0.68%, -0.32%) in the placebo group (estimated treatment difference, -0.57%; 95% confidence interval: -0.79%, -0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 12 May 2022; epub ahead of print
Zhu D, Li X, Ma J, Zeng J, ... Yang W, Chen L
Nat Med: 12 May 2022; epub ahead of print | PMID: 35551294
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Abstract

Modeling transmission of SARS-CoV-2 Omicron in China.

Cai J, Deng X, Yang J, Sun K, ... Ajelli M, Yu H
Having adopted a dynamic zero-COVID strategy to respond to SARS-CoV-2 variants with higher transmissibility since August 2021, China is now considering whether and for how long this policy can remain in place. The debate has thus shifted towards the identification of mitigation strategies for minimizing disruption to the healthcare system in the case of a nationwide epidemic. To this aim, we developed an age-structured stochastic compartmental susceptible-latent-infectious-removed-susceptible (SLIRS) model of SARS-CoV-2 transmission calibrated on the initial growth phase for the 2022 Omicron outbreak in Shanghai, to project COVID-19 burden (i.e., number of cases, patients requiring hospitalization and intensive care, and deaths) under hypothetical mitigation scenarios. The model also considers age-specific vaccine coverage data, vaccine efficacy against different clinical endpoints, waning of immunity, different antiviral therapies, and non-pharmaceutical interventions. We find that the level of immunity induced by the March 2022 vaccination campaign would be insufficient to prevent an Omicron wave that would result in exceeding critical care capacity with a projected intensive care unit peak demand of 15.6-times the existing capacity and causing approximately 1.55 million deaths. However, we also estimate that protecting vulnerable individuals by ensuring accessibility to vaccines and antiviral therapies, and maintaining implementation of non-pharmaceutical interventions could be sufficient to prevent overwhelming the healthcare system, suggesting that these factors should be points of emphasis in future mitigation policies.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 10 May 2022; epub ahead of print
Cai J, Deng X, Yang J, Sun K, ... Ajelli M, Yu H
Nat Med: 10 May 2022; epub ahead of print | PMID: 35537471
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Abstract

Spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals.

Brizzi A, Whittaker C, Servo LMS, Hawryluk I, ... Bhatt S, Ratmann O
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma variant of concern has spread rapidly across Brazil since late 2020, causing substantial infection and death waves. Here we used individual-level patient records after hospitalization with suspected or confirmed coronavirus disease 2019 (COVID-19) between 20 January 2020 and 26 July 2021 to document temporary, sweeping shocks in hospital fatality rates that followed the spread of Gamma across 14 state capitals, during which typically more than half of hospitalized patients aged 70 years and older died. We show that such extensive shocks in COVID-19 in-hospital fatality rates also existed before the detection of Gamma. Using a Bayesian fatality rate model, we found that the geographic and temporal fluctuations in Brazil\'s COVID-19 in-hospital fatality rates were primarily associated with geographic inequities and shortages in healthcare capacity. We estimate that approximately half of the COVID-19 deaths in hospitals in the 14 cities could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization and pandemic preparedness are critical to minimize population-wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries.

© 2022. The Author(s).

Nat Med: 10 May 2022; epub ahead of print
Brizzi A, Whittaker C, Servo LMS, Hawryluk I, ... Bhatt S, Ratmann O
Nat Med: 10 May 2022; epub ahead of print | PMID: 35538260
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Abstract

Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes.

Nair ATN, Wesolowska-Andersen A, Brorsson C, Rajendrakumar AL, ... Dennis JM, Pearson ER
Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 09 May 2022; epub ahead of print
Nair ATN, Wesolowska-Andersen A, Brorsson C, Rajendrakumar AL, ... Dennis JM, Pearson ER
Nat Med: 09 May 2022; epub ahead of print | PMID: 35534565
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Abstract

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.

Qi C, Gong J, Li J, Liu D, ... Li Z, Shen L
Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.

© 2022. The Author(s).

Nat Med: 09 May 2022; epub ahead of print
Qi C, Gong J, Li J, Liu D, ... Li Z, Shen L
Nat Med: 09 May 2022; epub ahead of print | PMID: 35534566
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Abstract

A T cell resilience model associated with response to immunotherapy in multiple tumor types.

Zhang Y, Trang V, Palmer DC, Kishton RJ, ... Guan XY, Jiang P
Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n = 38), infusion products for chimeric antigen receptor T cell therapies (n = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n = 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 02 May 2022; epub ahead of print
Zhang Y, Trang V, Palmer DC, Kishton RJ, ... Guan XY, Jiang P
Nat Med: 02 May 2022; epub ahead of print | PMID: 35501486
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Abstract

Unexplained post-acute infection syndromes.

Choutka J, Jansari V, Hornig M, Iwasaki A
SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.

© 2022. Springer Nature America, Inc.

Nat Med: 01 May 2022; 28:911-923
Choutka J, Jansari V, Hornig M, Iwasaki A
Nat Med: 01 May 2022; 28:911-923 | PMID: 35585196
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Abstract

Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI.

Vasey B, Nagendran M, Campbell B, Clifton DA, ... McCulloch P, DECIDE-AI expert group
A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico evaluation, but few have yet demonstrated real benefit to patient care. Early-stage clinical evaluation is important to assess an AI system\'s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use and pave the way to further large-scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multi-stakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two-round, modified Delphi process to collect and analyze expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 pre-defined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. In total, 123 experts participated in the first round of Delphi, 138 in the second round, 16 in the consensus meeting and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI-specific reporting items (made of 28 subitems) and ten generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we developed a guideline comprising key items that should be reported in early-stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 01 May 2022; 28:924-933
Vasey B, Nagendran M, Campbell B, Clifton DA, ... McCulloch P, DECIDE-AI expert group
Nat Med: 01 May 2022; 28:924-933 | PMID: 35585198
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Abstract

Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.

Chandran SS, Ma J, Klatt MG, Dündar F, ... Baker BM, Klebanoff CA
Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively \'featureless\' surface dominated by the peptide\'s backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.

© 2022. The Author(s).

Nat Med: 28 Apr 2022; epub ahead of print
Chandran SS, Ma J, Klatt MG, Dündar F, ... Baker BM, Klebanoff CA
Nat Med: 28 Apr 2022; epub ahead of print | PMID: 35484264
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Impact:
Abstract

Swarm learning for decentralized artificial intelligence in cancer histopathology.

Saldanha OL, Quirke P, West NP, James JA, ... Truhn D, Kather JN
Artificial intelligence (AI) can predict the presence of molecular alterations directly from routine histopathology slides. However, training robust AI systems requires large datasets for which data collection faces practical, ethical and legal obstacles. These obstacles could be overcome with swarm learning (SL), in which partners jointly train AI models while avoiding data transfer and monopolistic data governance. Here, we demonstrate the successful use of SL in large, multicentric datasets of gigapixel histopathology images from over 5,000 patients. We show that AI models trained using SL can predict BRAF mutational status and microsatellite instability directly from hematoxylin and eosin (H&E)-stained pathology slides of colorectal cancer. We trained AI models on three patient cohorts from Northern Ireland, Germany and the United States, and validated the prediction performance in two independent datasets from the United Kingdom. Our data show that SL-trained AI models outperform most locally trained models, and perform on par with models that are trained on the merged datasets. In addition, we show that SL-based AI models are data efficient. In the future, SL can be used to train distributed AI models for any histopathology image analysis task, eliminating the need for data transfer.

© 2022. The Author(s).

Nat Med: 25 Apr 2022; epub ahead of print
Saldanha OL, Quirke P, West NP, James JA, ... Truhn D, Kather JN
Nat Med: 25 Apr 2022; epub ahead of print | PMID: 35469069
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Impact:
Abstract

Digital remote monitoring plus usual care versus usual care in patients treated with oral anticancer agents: the randomized phase 3 CAPRI trial.

Mir O, Ferrua M, Fourcade A, Mathivon D, ... Di Palma M, Minvielle E
Strategies that individualize the care of cancer patients receiving oral anticancer agents offer opportunities to improve treatment adherence and patient care. However, the impact of digital remote monitoring systems in this setting has not been evaluated. Here, we report the results of a phase 3 trial (CAPRI, NCT02828462) to assess the impact of a nurse navigator-led program on treatment delivery for patients with metastatic cancer. Patients receiving approved oral anticancer agents were randomized (1:1) to an intervention combining a nurse navigator-led follow-up system and a web portal-smartphone application on top of usual care, or to usual symptom monitoring at the discretion of the treating oncologist, for a duration of 6 months. The primary objective included optimization of the treatment dose. Secondary objectives were grade ≥3 toxicities, patient experience, rates and duration of hospitalization, response and survival, and quality of life. In 559 evaluable patients the relative dose intensity was higher in the experimental arm (93.4% versus 89.4%, P = 0.04). The intervention improved the patient experience (Patient Assessment of Chronic Illness Care score, 2.94 versus 2.67, P = 0.01), reduced the days of hospitalization (2.82 versus 4.44 days, P = 0.02), and decreased treatment-related grade ≥3 toxicities (27.6% versus 36.9%, P = 0.02). These findings show that patient-centered care through remote monitoring of symptoms and treatment may improve patient outcomes and experience.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 25 Apr 2022; epub ahead of print
Mir O, Ferrua M, Fourcade A, Mathivon D, ... Di Palma M, Minvielle E
Nat Med: 25 Apr 2022; epub ahead of print | PMID: 35469070
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Impact:
Abstract

Effectiveness of a second BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60 years.

Arbel R, Sergienko R, Friger M, Peretz A, ... Netzer D, Hammerman A
The rapid emergence of the B.1.1.529 (Omicron) variant of SARS-CoV-2 led to a global resurgence of coronavirus disease 2019 (COVID-19). Israeli authorities approved a fourth COVID-19 vaccine dose (second-booster) for individuals aged 60 years and over who had received a first booster dose four or more months earlier. Evidence regarding the effectiveness of a second-booster dose in reducing hospitalizations and mortality due to COVID-19 is warranted. This retrospective cohort study included all members of Clalit Health Services, aged 60 to 100 years, who were eligible for the second-booster on January 3, 2022. Hospitalizations and mortality due to COVID-19 among participants who received the second-booster were compared with participants who received one booster dose. Cox proportional-hazards regression models with time-dependent covariates were used to estimate the association between the second-booster and hospitalizations and death due to COVID-19 while adjusting for demographic factors and coexisting illnesses. A total of 563,465 participants met the eligibility criteria. Of those, 328,597 (58%) received a second-booster dose during the 40-day study period. Hospitalizations due to COVID-19 occurred in 270 of the second-booster recipients and in 550 participants who received one booster dose (adjusted hazard ratio 0.36; 95% confidence interval (CI): 0.31 to 0.43). Death due to COVID-19 occurred in 92 second-booster recipients and in 232 participants who received one booster dose (adjusted hazard ratio 0.22; 95% CI 0.17 to 0.28). This study demonstrates a substantial reduction in hospitalizations and deaths due to Covid-19 conferred by a second-booster in Israeli adults aged 60 years and over.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 25 Apr 2022; epub ahead of print
Arbel R, Sergienko R, Friger M, Peretz A, ... Netzer D, Hammerman A
Nat Med: 25 Apr 2022; epub ahead of print | PMID: 35468276
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Impact:
Abstract

Development of a clinical polygenic risk score assay and reporting workflow.

Hao L, Kraft P, Berriz GF, Hynes ED, ... Vassy JL, Lebo MS
Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS-disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57-1.95) for type 2 diabetes to 2.38 (95% CI: 2.07-2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 18 Apr 2022; epub ahead of print
Hao L, Kraft P, Berriz GF, Hynes ED, ... Vassy JL, Lebo MS
Nat Med: 18 Apr 2022; epub ahead of print | PMID: 35437332
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Impact:
Abstract

Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial.

Kim ES, Velcheti V, Mekhail T, Yun C, ... Phan S, Socinski MA
Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

© 2022. The Author(s).

Nat Med: 14 Apr 2022; epub ahead of print
Kim ES, Velcheti V, Mekhail T, Yun C, ... Phan S, Socinski MA
Nat Med: 14 Apr 2022; epub ahead of print | PMID: 35422531
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Impact:
Abstract

Increased global integration in the brain after psilocybin therapy for depression.

Daws RE, Timmermann C, Giribaldi B, Sexton JD, ... Nutt D, Carhart-Harris R
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck\'s depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (\'psilocybin arm\') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (\'escitalopram arm\'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin\'s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 11 Apr 2022; epub ahead of print
Daws RE, Timmermann C, Giribaldi B, Sexton JD, ... Nutt D, Carhart-Harris R
Nat Med: 11 Apr 2022; epub ahead of print | PMID: 35411074
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Impact:
Abstract

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.

Fong S, Yates B, Sihn CR, Mattis AN, ... Pasi KJ, Wong WY
Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.

© 2022. The Author(s).

Nat Med: 11 Apr 2022; epub ahead of print
Fong S, Yates B, Sihn CR, Mattis AN, ... Pasi KJ, Wong WY
Nat Med: 11 Apr 2022; epub ahead of print | PMID: 35411075
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Impact:
Abstract

Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.

Casazza JP, Cale EM, Narpala S, Yamshchikov GV, ... Mascola JR, VRC 603 Study Team
Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial ( NCT03374202 ). AAV8-VRC07 was given at doses of 5 × 1010, 5 × 1011 and 2.5 × 1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1 µg ml-1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 11 Apr 2022; epub ahead of print
Casazza JP, Cale EM, Narpala S, Yamshchikov GV, ... Mascola JR, VRC 603 Study Team
Nat Med: 11 Apr 2022; epub ahead of print | PMID: 35411076
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Impact:
Abstract

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Monteiro C, Miarka L, Perea-García M, Priego N, ... RENACER, Valiente M
Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

© 2022. The Author(s).

Nat Med: 11 Apr 2022; epub ahead of print
Monteiro C, Miarka L, Perea-García M, Priego N, ... RENACER, Valiente M
Nat Med: 11 Apr 2022; epub ahead of print | PMID: 35411077
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Impact:
Abstract

Infectious viral load in unvaccinated and vaccinated individuals infected with ancestral, Delta or Omicron SARS-CoV-2.

Puhach O, Adea K, Hulo N, Sattonnet P, ... Eckerle I, Meyer B
Infectious viral load (VL) expelled as droplets and aerosols by infected individuals partly determines SARS-CoV-2 transmission. RNA VL measured by qRT-PCR is only a weak proxy for infectiousness. Studies on the kinetics of infectious VL are important to understand the mechanisms behind the different transmissibility of SARS-CoV-2 variants and the effect of vaccination on transmission, which allows to guide public health measures. In this study we quantified infectious VL in SARS-CoV-2 infected individuals during the first 5 symptomatic days by in vitro culturability assay in unvaccinated or vaccinated individuals infected with pre-variant of concern (pre-VOC) SARS-CoV-2, Delta, or Omicron. Unvaccinated individuals infected with pre-VOC SARS-CoV-2 had lower infectious VL compared to Delta-infected unvaccinated individuals. Full vaccination (defined as >2weeks after reception of 2nd dose during primary vaccination series) significantly reduced infectious VL for Delta breakthrough cases compared to unvaccinated individuals. For Omicron breakthrough cases, reduced infectious VL was only observed in boosted but not in fully vaccinated individuals compared to unvaccinated subjects. In addition, infectious VL was lower in fully vaccinated Omicron- compared to fully vaccinated Delta-infected individuals, suggesting that other mechanisms than increased infectious VL contribute to the high infectiousness of SARS-CoV-2 Omicron. Our findings indicate that vaccines may lower transmission risk and therefore have a public health benefit beyond the individual protection from severe disease.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 08 Apr 2022; epub ahead of print
Puhach O, Adea K, Hulo N, Sattonnet P, ... Eckerle I, Meyer B
Nat Med: 08 Apr 2022; epub ahead of print | PMID: 35395151
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Impact:
Abstract

Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes.

Shaked A, Loza BL, Van Loon E, Olthoff KM, ... Asrani SK, Keating BJ
Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10-7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 07 Apr 2022; epub ahead of print
Shaked A, Loza BL, Van Loon E, Olthoff KM, ... Asrani SK, Keating BJ
Nat Med: 07 Apr 2022; epub ahead of print | PMID: 35393535
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Impact:
Abstract

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.

Russell SR, Drack AV, Cideciyan AV, Jacobson SG, ... Rodman D, Girach A
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

© 2022. The Author(s).

Nat Med: 04 Apr 2022; epub ahead of print
Russell SR, Drack AV, Cideciyan AV, Jacobson SG, ... Rodman D, Girach A
Nat Med: 04 Apr 2022; epub ahead of print | PMID: 35379979
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Impact:
Abstract

Priorities for cancer research in low- and middle-income countries: a global perspective.

Pramesh CS, Badwe RA, Bhoo-Pathy N, Booth CM, ... Varghese C, Weiderpass E
Cancer research currently is heavily skewed toward high-income countries (HICs), with little research conducted in, and relevant to, the problems of low- and middle-income countries (LMICs). This regional discordance in cancer knowledge generation and application needs to be rebalanced. Several gaps in the research enterprise of LMICs need to be addressed to promote regionally relevant research, and radical rethinking is needed to address the burning issues in cancer care in these regions. We identified five top priorities in cancer research in LMICs based on current and projected needs: reducing the burden of patients with advanced disease; improving access and affordability, and outcomes of cancer treatment; value-based care and health economics; quality improvement and implementation research; and leveraging technology to improve cancer control. LMICs have an excellent opportunity to address important questions in cancer research that could impact cancer control globally. Success will require collaboration and commitment from governments, policy makers, funding agencies, health care organizations and leaders, researchers and the public.

© 2022. Springer Nature America, Inc.

Nat Med: 31 Mar 2022; 28:649-657
Pramesh CS, Badwe RA, Bhoo-Pathy N, Booth CM, ... Varghese C, Weiderpass E
Nat Med: 31 Mar 2022; 28:649-657 | PMID: 35440716
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Impact:
Abstract

Delivering precision oncology to patients with cancer.

Mateo J, Steuten L, Aftimos P, André F, ... Westphalen CB, Voest E
With the increasing use of genomic profiling for diagnosis and therapy guidance in many tumor types, precision oncology is rapidly reshaping cancer care. However, the current trajectory of drug development in oncology results in a paradox: if patients cannot access advanced diagnostics, we may be developing drugs that will reach few patients. In this Perspective, we outline the major challenges to the implementation of precision oncology and discuss critical steps toward resolving these, including facilitation of equal access to genomics tests, ensuring that clinical studies provide robust evidence for new drugs and technologies, enabling physicians to interpret genomics data, and empowering patients toward shared decision-making. A multi-stakeholder approach to evidence generation, value assessment, and healthcare delivery is necessary to translate advances in precision oncology into benefits for patients with cancer globally.

© 2022. Springer Nature America, Inc.

Nat Med: 31 Mar 2022; 28:658-665
Mateo J, Steuten L, Aftimos P, André F, ... Westphalen CB, Voest E
Nat Med: 31 Mar 2022; 28:658-665 | PMID: 35440717
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Impact:
Abstract

The future of early cancer detection.

Fitzgerald RC, Antoniou AC, Fruk L, Rosenfeld N
A proactive approach to detecting cancer at an early stage can make treatments more effective, with fewer side effects and improved long-term survival. However, as detection methods become increasingly sensitive, it can be difficult to distinguish inconsequential changes from lesions that will lead to life-threatening cancer. Progress relies on a detailed understanding of individualized risk, clear delineation of cancer development stages, a range of testing methods with optimal performance characteristics, and robust evaluation of the implications for individuals and society. In the future, advances in sensors, contrast agents, molecular methods, and artificial intelligence will help detect cancer-specific signals in real time. To reduce the burden of cancer on society, risk-based detection and prevention needs to be cost effective and widely accessible.

© 2022. Springer Nature America, Inc.

Nat Med: 31 Mar 2022; 28:666-677
Fitzgerald RC, Antoniou AC, Fruk L, Rosenfeld N
Nat Med: 31 Mar 2022; 28:666-677 | PMID: 35440720
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Impact:
Abstract

Engineered cellular immunotherapies in cancer and beyond.

Finck AV, Blanchard T, Roselle CP, Golinelli G, June CH
This year marks the tenth anniversary of cell therapy with chimeric antigen receptor (CAR)-modified T cells for refractory leukemia. The widespread commercial approval of genetically engineered T cells for a variety of blood cancers offers hope for patients with other types of cancer, and the convergence of human genome engineering and cell therapy technology holds great potential for generation of a new class of cellular therapeutics. In this Review, we discuss the goals of cellular immunotherapy in cancer, key challenges facing the field and exciting strategies that are emerging to overcome these obstacles. Finally, we outline how developments in the cancer field are paving the way for cellular immunotherapeutics in other diseases.

© 2022. Springer Nature America, Inc.

Nat Med: 31 Mar 2022; 28:678-689
Finck AV, Blanchard T, Roselle CP, Golinelli G, June CH
Nat Med: 31 Mar 2022; 28:678-689 | PMID: 35440724
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Impact:
Abstract

Targeting the gut and tumor microbiota in cancer.

Park EM, Chelvanambi M, Bhutiani N, Kroemer G, Zitvogel L, Wargo JA
Microorganisms within the gut and other niches may contribute to carcinogenesis, as well as shaping cancer immunosurveillance and response to immunotherapy. Our understanding of the complex relationship between different host-intrinsic microorganisms, as well as the multifaceted mechanisms by which they influence health and disease, has grown tremendously-hastening development of novel therapeutic strategies that target the microbiota to improve treatment outcomes in cancer. Accordingly, the evaluation of a patient\'s microbial composition and function and its subsequent targeted modulation represent key elements of future multidisciplinary and precision-medicine approaches. In this Review, we outline the current state of research toward harnessing the microbiome to better prevent and treat cancer.

© 2022. Springer Nature America, Inc.

Nat Med: 31 Mar 2022; 28:690-703
Park EM, Chelvanambi M, Bhutiani N, Kroemer G, Zitvogel L, Wargo JA
Nat Med: 31 Mar 2022; 28:690-703 | PMID: 35440726
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Impact:
Abstract

Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults.

Killingley B, Mann AJ, Kalinova M, Boyers A, ... Catchpole AP, Chiu C
Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237 ; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study\'s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2-4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 31 Mar 2022; epub ahead of print
Killingley B, Mann AJ, Kalinova M, Boyers A, ... Catchpole AP, Chiu C
Nat Med: 31 Mar 2022; epub ahead of print | PMID: 35361992
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Abstract

Suicide risk and mortality among patients with cancer.

Heinrich M, Hofmann L, Baurecht H, Kreuzer PM, ... Leitzmann MF, Seliger C
Despite substantial progress in cancer therapy in recent decades, patients with cancer remain at high suicide risk. Data from individual studies have not been comprehensively quantified and specific risk factors are ill-defined. We assessed suicide mortality risk according to cancer prognosis, stage, time since diagnosis, gender, ethnicity, marital status, year of recruitment and geographic region. We searched EMBASE, MEDLINE, PsycINFO, Web of Science, CINAHL and Google Scholar for relevant articles up to February 2021. We used a random effects model, performed meta-regression meta-analysis and assessed heterogeneity and publication bias using I², funnel plots and Egger\'s and Begg\'s tests. We performed a systematic review including 62 studies and 46,952,813 patients. To avoid patient sample overlap, the meta-analysis was performed on 28 studies, involving 22,407,690 patients with cancer. Suicide mortality was significantly increased compared with the general population (standardized mortality ratio = 1.85, 95% confidence interval = 1.55-2.20). Risk was strongly related to cancer prognosis, cancer stage, time since diagnosis and geographic region. Patients with cancer, particularly those with specific risk factors, should be closely monitored for suicidality and need specialized care to reduce short- and long-term risks of suicide.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 28 Mar 2022; epub ahead of print
Heinrich M, Hofmann L, Baurecht H, Kreuzer PM, ... Leitzmann MF, Seliger C
Nat Med: 28 Mar 2022; epub ahead of print | PMID: 35347279
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Abstract

Cumulative burden of psychiatric disorders and self-harm across 26 adult cancers.

Chang WH, Lai AG
Cancer is a life-altering event causing considerable psychological distress. However, information on the total burden of psychiatric disorders across all common adult cancers and therapy exposures has remained scarce. Here, we estimated the risk of self-harm after incident psychiatric disorder diagnosis in patients with cancer and the risk of unnatural deaths after self-harm in 459,542 individuals. Depression was the most common psychiatric disorder in patients with cancer. Patients who received chemotherapy, radiotherapy and surgery had the highest cumulative burden of psychiatric disorders. Patients treated with alkylating agent chemotherapeutics had the highest burden of psychiatric disorders, whereas those treated with kinase inhibitors had the lowest burden. All mental illnesses were associated with an increased risk of subsequent self-harm, where the highest risk was observed within 12 months of the mental illness diagnosis. Patients who harmed themselves were 6.8 times more likely to die of unnatural causes of death compared with controls within 12 months of self-harm (hazard ratio (HR), 6.8; 95% confidence interval (CI), 4.3-10.7). The risk of unnatural death after 12 months was markedly lower (HR, 2.0; 95% CI, 1.5-2.7). We provide an extensive knowledge base to help inform collaborative cancer-psychiatric care initiatives by prioritizing patients who are most at risk.

© 2022. The Author(s).

Nat Med: 28 Mar 2022; epub ahead of print
Chang WH, Lai AG
Nat Med: 28 Mar 2022; epub ahead of print | PMID: 35347280
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Abstract

In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial.

Gurevich I, Agarwal P, Zhang P, Dolorito JA, ... Krishnan SM, Marinkovich MP
Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain-severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 28 Mar 2022; epub ahead of print
Gurevich I, Agarwal P, Zhang P, Dolorito JA, ... Krishnan SM, Marinkovich MP
Nat Med: 28 Mar 2022; epub ahead of print | PMID: 35347281
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Abstract

Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies.

Bruel T, Hadjadj J, Maes P, Planas D, ... Prazuck T, Schwartz O
The severe acute respiratory syndrome coronavirus 2 Omicron BA.1 sublineage has been supplanted in many countries by the BA.2 sublineage. BA.2 differs from BA.1 by about 21 mutations in its spike. In this study, we first compared the sensitivity of BA.1 and BA.2 to neutralization by nine therapeutic monoclonal antibodies (mAbs). In contrast to BA.1, BA.2 was sensitive to cilgavimab, partly inhibited by imdevimab and resistant to adintrevimab and sotrovimab. We then analyzed sera from 29 immunocompromised individuals up to 1 month after administration of Ronapreve (casirivimab and imdevimab) and/or Evusheld (cilgavimab and tixagevimab) antibody cocktails. All treated individuals displayed elevated antibody levels in their sera, which efficiently neutralized the Delta variant. Sera from Ronapreve recipients did not neutralize BA.1 and weakly inhibited BA.2. Neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 Evusheld recipients, respectively. As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (nine-fold). We further report four breakthrough Omicron infections among the 29 individuals, indicating that antibody treatment did not fully prevent infection. Collectively, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron neutralizing activity of Ronapreve and, to a lesser extent, that of Evusheld is reduced in patients\' sera.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 23 Mar 2022; epub ahead of print
Bruel T, Hadjadj J, Maes P, Planas D, ... Prazuck T, Schwartz O
Nat Med: 23 Mar 2022; epub ahead of print | PMID: 35322239
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Abstract

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

Kachroo P, Stewart ID, Kelly RS, Stav M, ... Langenberg C, Lasky-Su JA
The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 21 Mar 2022; epub ahead of print
Kachroo P, Stewart ID, Kelly RS, Stav M, ... Langenberg C, Lasky-Su JA
Nat Med: 21 Mar 2022; epub ahead of print | PMID: 35314841
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Impact:
Abstract

Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial.

Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, ... Xu H, Chavez JC
High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients (n = 37) was met, with 78% CRR (95% confidence interval (CI), 62-90) and 89% ORR (95% CI, 75-97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile.

© 2022. The Author(s).

Nat Med: 21 Mar 2022; epub ahead of print
Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, ... Xu H, Chavez JC
Nat Med: 21 Mar 2022; epub ahead of print | PMID: 35314842
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Abstract

PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, ... Fraietta JA, Haas NB
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 21 Mar 2022; epub ahead of print
Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, ... Fraietta JA, Haas NB
Nat Med: 21 Mar 2022; epub ahead of print | PMID: 35314843
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Abstract

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

Carapito R, Aouadi I, Verniquet M, Untrau M, ... Süsal C, Bahram S
The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.

© 2022. The Author(s).

Nat Med: 13 Mar 2022; epub ahead of print
Carapito R, Aouadi I, Verniquet M, Untrau M, ... Süsal C, Bahram S
Nat Med: 13 Mar 2022; epub ahead of print | PMID: 35288692
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Abstract

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.

Khabirova E, Jardine L, Coorens THH, Webb S, ... Haniffa M, Behjati S
KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.

© 2022. The Author(s).

Nat Med: 13 Mar 2022; epub ahead of print
Khabirova E, Jardine L, Coorens THH, Webb S, ... Haniffa M, Behjati S
Nat Med: 13 Mar 2022; epub ahead of print | PMID: 35288693
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Abstract

Pancreatic islet cryopreservation by vitrification achieves high viability, function, recovery and clinical scalability for transplantation.

Zhan L, Rao JS, Sethia N, Slama MQ, ... Bischof JC, Finger EB
Pancreatic islet transplantation can cure diabetes but requires accessible, high-quality islets in sufficient quantities. Cryopreservation could solve islet supply chain challenges by enabling quality-controlled banking and pooling of donor islets. Unfortunately, cryopreservation has not succeeded in this objective, as it must simultaneously provide high recovery, viability, function and scalability. Here, we achieve this goal in mouse, porcine, human and human stem cell (SC)-derived beta cell (SC-beta) islets by comprehensive optimization of cryoprotectant agent (CPA) composition, CPA loading and unloading conditions and methods for vitrification and rewarming (VR). Post-VR islet viability, relative to control, was 90.5% for mouse, 92.1% for SC-beta, 87.2% for porcine and 87.4% for human islets, and it remained unchanged for at least 9 months of cryogenic storage. VR islets had normal macroscopic, microscopic, and ultrastructural morphology. Mitochondrial membrane potential and adenosine triphosphate (ATP) levels were slightly reduced, but all other measures of cellular respiration, including oxygen consumption rate (OCR) to produce ATP, were unchanged. VR islets had normal glucose-stimulated insulin secretion (GSIS) function in vitro and in vivo. Porcine and SC-beta islets made insulin in xenotransplant models, and mouse islets tested in a marginal mass syngeneic transplant model cured diabetes in 92% of recipients within 24-48 h after transplant. Excellent glycemic control was seen for 150 days. Finally, our approach processed 2,500 islets with >95% islets recovery at >89% post-thaw viability and can readily be scaled up for higher throughput. These results suggest that cryopreservation can now be used to supply needed islets for improved transplantation outcomes that cure diabetes.

© 2022. The Author(s).

Nat Med: 13 Mar 2022; epub ahead of print
Zhan L, Rao JS, Sethia N, Slama MQ, ... Bischof JC, Finger EB
Nat Med: 13 Mar 2022; epub ahead of print | PMID: 35288694
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Abstract

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Smith M, Dai A, Ghilardi G, Amelsberg KV, ... van den Brink MRM, Ruella M
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 13 Mar 2022; epub ahead of print
Smith M, Dai A, Ghilardi G, Amelsberg KV, ... van den Brink MRM, Ruella M
Nat Med: 13 Mar 2022; epub ahead of print | PMID: 35288695
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Abstract

COVID-19 and resilience of healthcare systems in ten countries.

Arsenault C, Gage A, Kim MK, Kapoor NR, ... Bauhoff S, Kruk ME
Declines in health service use during the Coronavirus Disease 2019 (COVID-19) pandemic could have important effects on population health. In this study, we used an interrupted time series design to assess the immediate effect of the pandemic on 31 health services in two low-income (Ethiopia and Haiti), six middle-income (Ghana, Lao People\'s Democratic Republic, Mexico, Nepal, South Africa and Thailand) and high-income (Chile and South Korea) countries. Despite efforts to maintain health services, disruptions of varying magnitude and duration were found in every country, with no clear patterns by country income group or pandemic intensity. Disruptions in health services often preceded COVID-19 waves. Cancer screenings, TB screening and detection and HIV testing were most affected (26-96% declines). Total outpatient visits declined by 9-40% at national levels and remained lower than predicted by the end of 2020. Maternal health services were disrupted in approximately half of the countries, with declines ranging from 5% to 33%. Child vaccinations were disrupted for shorter periods, but we estimate that catch-up campaigns might not have reached all children missed. By contrast, provision of antiretrovirals for HIV was not affected. By the end of 2020, substantial disruptions remained in half of the countries. Preliminary data for 2021 indicate that disruptions likely persisted. Although a portion of the declines observed might result from decreased needs during lockdowns (from fewer infectious illnesses or injuries), a larger share likely reflects a shortfall of health system resilience. Countries must plan to compensate for missed healthcare during the current pandemic and invest in strategies for better health system resilience for future emergencies.

© 2022. The Author(s).

Nat Med: 13 Mar 2022; epub ahead of print
Arsenault C, Gage A, Kim MK, Kapoor NR, ... Bauhoff S, Kruk ME
Nat Med: 13 Mar 2022; epub ahead of print | PMID: 35288697
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Impact:
Abstract

Misinformation: susceptibility, spread, and interventions to immunize the public.

van der Linden S
The spread of misinformation poses a considerable threat to public health and the successful management of a global pandemic. For example, studies find that exposure to misinformation can undermine vaccination uptake and compliance with public-health guidelines. As research on the science of misinformation is rapidly emerging, this conceptual Review summarizes what we know along three key dimensions of the infodemic: susceptibility, spread, and immunization. Extant research is evaluated on the questions of why (some) people are (more) susceptible to misinformation, how misinformation spreads in online social networks, and which interventions can help to boost psychological immunity to misinformation. Implications for managing the infodemic are discussed.

© 2022. Springer Nature America, Inc.

Nat Med: 09 Mar 2022; epub ahead of print
van der Linden S
Nat Med: 09 Mar 2022; epub ahead of print | PMID: 35273402
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Impact:
Abstract

An epidemic of uncertainty: rumors, conspiracy theories and vaccine hesitancy.

Pertwee E, Simas C, Larson HJ
The COVID-19 \'infodemic\' continues to undermine trust in vaccination efforts aiming to bring an end to the pandemic. However, the challenge of vaccine hesitancy is not only a problem of the information ecosystem and it often has little to do with the vaccines themselves. In this Perspective, we argue that the epidemiological and social crises brought about by COVID-19 have magnified widely held social anxieties and trust issues that, in the unique circumstances of this global pandemic, have exacerbated skepticism toward vaccines. We argue that trust is key to overcoming vaccine hesitancy, especially in a context of widespread social uncertainty brought about by the pandemic, where public sentiment can be volatile. Finally, we draw out some implications of our argument for strategies to build vaccine confidence.

© 2022. Springer Nature America, Inc.

Nat Med: 09 Mar 2022; epub ahead of print
Pertwee E, Simas C, Larson HJ
Nat Med: 09 Mar 2022; epub ahead of print | PMID: 35273403
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Impact:
Abstract

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.

Jasra S, Giricz O, Zeig-Owens R, Pradhan K, ... Prezant DJ, Verma A
The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 06 Mar 2022; epub ahead of print
Jasra S, Giricz O, Zeig-Owens R, Pradhan K, ... Prezant DJ, Verma A
Nat Med: 06 Mar 2022; epub ahead of print | PMID: 35256801
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Impact:
Abstract

Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy.

Ganan-Gomez I, Yang H, Ma F, Montalban-Bravo G, ... Garcia-Manero G, Colla S
Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

© 2022. The Author(s).

Nat Med: 02 Mar 2022; epub ahead of print
Ganan-Gomez I, Yang H, Ma F, Montalban-Bravo G, ... Garcia-Manero G, Colla S
Nat Med: 02 Mar 2022; epub ahead of print | PMID: 35241842
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Impact:
Abstract

Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial.

Chu L, Vrbicky K, Montefiori D, Huang W, ... Leav B, McPhee R
Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6-8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 ( NCT04405076 ). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.

© 2022. The Author(s).

Nat Med: 02 Mar 2022; epub ahead of print
Chu L, Vrbicky K, Montefiori D, Huang W, ... Leav B, McPhee R
Nat Med: 02 Mar 2022; epub ahead of print | PMID: 35241844
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Abstract

Whole-genome risk prediction of common diseases in human preimplantation embryos.

Kumar A, Im K, Banjevic M, Ng PC, ... Klatsky PC, Rabinowitz M
Preimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0-99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2-99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice.

© 2022. The Author(s).

Nat Med: 28 Feb 2022; 28:513-516
Kumar A, Im K, Banjevic M, Ng PC, ... Klatsky PC, Rabinowitz M
Nat Med: 28 Feb 2022; 28:513-516 | PMID: 35314819
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Abstract

Deep learning-enabled assessment of cardiac allograft rejection from endomyocardial biopsies.

Lipkova J, Chen TY, Lu MY, Chen RJ, ... Odening KE, Mahmood F
Endomyocardial biopsy (EMB) screening represents the standard of care for detecting allograft rejections after heart transplant. Manual interpretation of EMBs is affected by substantial interobserver and intraobserver variability, which often leads to inappropriate treatment with immunosuppressive drugs, unnecessary follow-up biopsies and poor transplant outcomes. Here we present a deep learning-based artificial intelligence (AI) system for automated assessment of gigapixel whole-slide images obtained from EMBs, which simultaneously addresses detection, subtyping and grading of allograft rejection. To assess model performance, we curated a large dataset from the United States, as well as independent test cohorts from Turkey and Switzerland, which includes large-scale variability across populations, sample preparations and slide scanning instrumentation. The model detects allograft rejection with an area under the receiver operating characteristic curve (AUC) of 0.962; assesses the cellular and antibody-mediated rejection type with AUCs of 0.958 and 0.874, respectively; detects Quilty B lesions, benign mimics of rejection, with an AUC of 0.939; and differentiates between low-grade and high-grade rejections with an AUC of 0.833. In a human reader study, the AI system showed non-inferior performance to conventional assessment and reduced interobserver variability and assessment time. This robust evaluation of cardiac allograft rejection paves the way for clinical trials to establish the efficacy of AI-assisted EMB assessment and its potential for improving heart transplant outcomes.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 28 Feb 2022; 28:575-582
Lipkova J, Chen TY, Lu MY, Chen RJ, ... Odening KE, Mahmood F
Nat Med: 28 Feb 2022; 28:575-582 | PMID: 35314822
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Abstract

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma.

Lee KA, Thomas AM, Bolte LA, Björk JR, ... Weersma RK, Segata N
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

© 2022. The Author(s).

Nat Med: 27 Feb 2022; epub ahead of print
Lee KA, Thomas AM, Bolte LA, Björk JR, ... Weersma RK, Segata N
Nat Med: 27 Feb 2022; epub ahead of print | PMID: 35228751
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Abstract

Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1.

McCulloch JA, Davar D, Rodrigues RR, Badger JH, ... Trinchieri G, Dzutsev AK
Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Nat Med: 27 Feb 2022; epub ahead of print
McCulloch JA, Davar D, Rodrigues RR, Badger JH, ... Trinchieri G, Dzutsev AK
Nat Med: 27 Feb 2022; epub ahead of print | PMID: 35228752
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Abstract

The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial.

Spertus JA, Birmingham MC, Nassif M, Damaraju CV, ... Kosiborod MN, Januzzi JL
Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8-7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.

© 2022. The Author(s).

Nat Med: 27 Feb 2022; epub ahead of print
Spertus JA, Birmingham MC, Nassif M, Damaraju CV, ... Kosiborod MN, Januzzi JL
Nat Med: 27 Feb 2022; epub ahead of print | PMID: 35228753
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Abstract

The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.

Voors AA, Angermann CE, Teerlink JR, Collins SP, ... Salsali A, Ponikowski P
The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

© 2022. The Author(s).

Nat Med: 27 Feb 2022; epub ahead of print
Voors AA, Angermann CE, Teerlink JR, Collins SP, ... Salsali A, Ponikowski P
Nat Med: 27 Feb 2022; epub ahead of print | PMID: 35228754
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Abstract

Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial.

Dizman N, Meza L, Bergerot P, Alcantara M, ... Highlander SK, Pal SK
Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab-ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab-ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05-0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab-ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

© 2022. The Author(s).

Nat Med: 27 Feb 2022; epub ahead of print
Dizman N, Meza L, Bergerot P, Alcantara M, ... Highlander SK, Pal SK
Nat Med: 27 Feb 2022; epub ahead of print | PMID: 35228755
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Abstract

Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis.

Sattar N, McGuire DK, Pavo I, Weerakkody GJ, ... Wiese RJ, Zoungas S
Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.

© 2022. The Author(s).

Nat Med: 23 Feb 2022; epub ahead of print
Sattar N, McGuire DK, Pavo I, Weerakkody GJ, ... Wiese RJ, Zoungas S
Nat Med: 23 Feb 2022; epub ahead of print | PMID: 35210595
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Abstract

Modeling comparative cost-effectiveness of SARS-CoV-2 vaccine dose fractionation in India.

Du Z, Wang L, Pandey A, Lim WW, ... Cobey S, Cowling BJ
Given global Coronavirus Disease 2019 (COVID-19) vaccine shortages and inequity of vaccine distributions, fractionation of vaccine doses might be an effective strategy for reducing public health and economic burden, notwithstanding the emergence of new variants of concern. In this study, we developed a multi-scale model incorporating population-level transmission and individual-level vaccination to estimate the costs of hospitalization and vaccination and the economic benefits of reducing COVID-19 deaths due to dose-fractionation strategies in India. We used large-scale survey data of the willingness to pay together with data of vaccine and hospital admission costs to build the model. We found that fractional doses of vaccines could be an economically viable vaccination strategy compared to alternatives of either full-dose vaccination or no vaccination. Dose-sparing strategies could save a large number of lives, even with the emergence of new variants with higher transmissibility.

© 2022. The Author(s).

Nat Med: 23 Feb 2022; epub ahead of print
Du Z, Wang L, Pandey A, Lim WW, ... Cobey S, Cowling BJ
Nat Med: 23 Feb 2022; epub ahead of print | PMID: 35210596
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This program is still in alpha version.