Journal: Nat Med

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Abstract
<div><h4>Persistent mutation burden drives sustained anti-tumor immune responses.</h4><i>Niknafs N, Balan A, Cherry C, Hummelink K, ... Velculescu VE, Anagnostou V</i><br /><AbstractText>Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 26 Jan 2023; epub ahead of print</small></div>
Niknafs N, Balan A, Cherry C, Hummelink K, ... Velculescu VE, Anagnostou V
Nat Med: 26 Jan 2023; epub ahead of print | PMID: 36702947
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<div><h4>Early detection of visual impairment in young children using a smartphone-based deep learning system.</h4><i>Chen W, Li R, Yu Q, Xu A, ... Ding X, Lin H</i><br /><AbstractText>Early detection of visual impairment is crucial but is frequently missed in young children, who are capable of only limited cooperation with standard vision tests. Although certain features of visually impaired children, such as facial appearance and ocular movements, can assist ophthalmic practice, applying these features to real-world screening remains challenging. Here, we present a mobile health (mHealth) system, the smartphone-based Apollo Infant Sight (AIS), which identifies visually impaired children with any of 16 ophthalmic disorders by recording and analyzing their gazing behaviors and facial features under visual stimuli. Videos from 3,652 children (≤48 months in age; 54.5% boys) were prospectively collected to develop and validate this system. For detecting visual impairment, AIS achieved an area under the receiver operating curve (AUC) of 0.940 in an internal validation set and an AUC of 0.843 in an external validation set collected in multiple ophthalmology clinics across China. In a further test of AIS for at-home implementation by untrained parents or caregivers using their smartphones, the system was able to adapt to different testing conditions and achieved an AUC of 0.859. This mHealth system has the potential to be used by healthcare professionals, parents and caregivers for identifying young children with visual impairment across a wide range of ophthalmic disorders.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 26 Jan 2023; epub ahead of print</small></div>
Chen W, Li R, Yu Q, Xu A, ... Ding X, Lin H
Nat Med: 26 Jan 2023; epub ahead of print | PMID: 36702948
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<div><h4>Combined PD-1, BRAF and MEK inhibition in BRAF colorectal cancer: a phase 2 trial.</h4><i>Tian J, Chen JH, Chao SX, Pelka K, ... Hacohen N, Corcoran RB</i><br /><AbstractText>While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF<sup>V600E</sup> colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF<sup>V600E</sup> CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 26 Jan 2023; epub ahead of print</small></div>
Tian J, Chen JH, Chao SX, Pelka K, ... Hacohen N, Corcoran RB
Nat Med: 26 Jan 2023; epub ahead of print | PMID: 36702949
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<div><h4>Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.</h4><i>Mailankody S, Matous JV, Chhabra S, Liedtke M, ... Balakumaran A, Kumar SK</i><br /><AbstractText>ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 10<sup>6</sup> CAR<sup>+</sup> T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen (n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 23 Jan 2023; epub ahead of print</small></div>
Mailankody S, Matous JV, Chhabra S, Liedtke M, ... Balakumaran A, Kumar SK
Nat Med: 23 Jan 2023; epub ahead of print | PMID: 36690811
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<div><h4>Federated learning for predicting histological response to neoadjuvant chemotherapy in triple-negative breast cancer.</h4><i>Ogier du Terrail J, Leopold A, Joly C, Béguier C, ... Bataillon G, Heudel PE</i><br /><AbstractText>Triple-negative breast cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options. The current standard of care in nonmetastatic settings is neoadjuvant chemotherapy (NACT), but treatment efficacy varies substantially across patients. This heterogeneity is still poorly understood, partly due to the paucity of curated TNBC data. Here we investigate the use of machine learning (ML) leveraging whole-slide images and clinical information to predict, at diagnosis, the histological response to NACT for early TNBC women patients. To overcome the biases of small-scale studies while respecting data privacy, we conducted a multicentric TNBC study using federated learning, in which patient data remain secured behind hospitals\' firewalls. We show that local ML models relying on whole-slide images can predict response to NACT but that collaborative training of ML models further improves performance, on par with the best current approaches in which ML models are trained using time-consuming expert annotations. Our ML model is interpretable and is sensitive to specific histological patterns. This proof of concept study, in which federated learning is applied to real-world datasets, paves the way for future biomarker discovery using unprecedentedly large datasets.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Ogier du Terrail J, Leopold A, Joly C, Béguier C, ... Bataillon G, Heudel PE
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658418
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<div><h4>Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death.</h4><i>Byrne AB, Arts P, Ha TT, Kassahn KS, ... Barnett CP, Scott HS</i><br /><AbstractText>Pregnancy loss and perinatal death are devastating events for families. We assessed \'genomic autopsy\' as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.</AbstractText><br /><br />© 2023. Crown.<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Byrne AB, Arts P, Ha TT, Kassahn KS, ... Barnett CP, Scott HS
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658419
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<div><h4>A wearable motion capture suit and machine learning predict disease progression in Friedreich\'s ataxia.</h4><i>Kadirvelu B, Gavriel C, Nageshwaran S, Chan JPK, ... Festenstein R, Faisal AA</i><br /><AbstractText>Friedreich\'s ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Kadirvelu B, Gavriel C, Nageshwaran S, Chan JPK, ... Festenstein R, Faisal AA
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658420
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<div><h4>Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy.</h4><i>Ricotti V, Kadirvelu B, Selby V, Festenstein R, ... Voit T, Faisal AA</i><br /><AbstractText>Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Ricotti V, Kadirvelu B, Selby V, Festenstein R, ... Voit T, Faisal AA
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658421
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<div><h4>Bodywide ecological interventions on cancer.</h4><i>Kroemer G, McQuade JL, Merad M, André F, Zitvogel L</i><br /><AbstractText>Historically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries-all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body \'ecological\' exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Kroemer G, McQuade JL, Merad M, André F, Zitvogel L
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658422
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<div><h4>The impact of the COVID-19 pandemic on cardiovascular disease prevention and management.</h4><i>Dale CE, Takhar R, Carragher R, Katsoulis M, ... Sofat R, CVD-COVID-UK Consortium</i><br /><AbstractText>How the Coronavirus Disease 2019 (COVID-19) pandemic has affected prevention and management of cardiovascular disease (CVD) is not fully understood. In this study, we used medication data as a proxy for CVD management using routinely collected, de-identified, individual-level data comprising 1.32 billion records of community-dispensed CVD medications from England, Scotland and Wales between April 2018 and July 2021. Here we describe monthly counts of prevalent and incident medications dispensed, as well as percentage changes compared to the previous year, for several CVD-related indications, focusing on hypertension, hypercholesterolemia and diabetes. We observed a decline in the dispensing of antihypertensive medications between March 2020 and July 2021, with 491,306 fewer individuals initiating treatment than expected. This decline was predicted to result in 13,662 additional CVD events, including 2,281 cases of myocardial infarction and 3,474 cases of stroke, should individuals remain untreated over their lifecourse. Incident use of lipid-lowering medications decreased by 16,744 patients per month during the first half of 2021 as compared to 2019. By contrast, incident use of medications to treat type 2 diabetes mellitus, other than insulin, increased by approximately 623 patients per month for the same time period. In light of these results, methods to identify and treat individuals who have missed treatment for CVD risk factors and remain undiagnosed are urgently required to avoid large numbers of excess future CVD events, an indirect impact of the COVID-19 pandemic.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Dale CE, Takhar R, Carragher R, Katsoulis M, ... Sofat R, CVD-COVID-UK Consortium
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658423
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<div><h4>Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.</h4><i>Yap TA, Daver N, Mahendra M, Zhang J, ... Marszalek JR, Konopleva M</i><br /><AbstractText>Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 19 Jan 2023; epub ahead of print</small></div>
Yap TA, Daver N, Mahendra M, Zhang J, ... Marszalek JR, Konopleva M
Nat Med: 19 Jan 2023; epub ahead of print | PMID: 36658425
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<div><h4>Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases.</h4><i>Kiiskinen T, Helkkula P, Krebs K, Karjalainen J, ... Milani L, Ripatti S</i><br /><AbstractText>Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10<sup>-9</sup>) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 18 Jan 2023; epub ahead of print</small></div>
Kiiskinen T, Helkkula P, Krebs K, Karjalainen J, ... Milani L, Ripatti S
Nat Med: 18 Jan 2023; epub ahead of print | PMID: 36653479
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<div><h4>Real-world COVID-19 vaccine effectiveness against the Omicron BA.2 variant in a SARS-CoV-2 infection-naive population.</h4><i>Lau JJ, Cheng SMS, Leung K, Lee CK, ... Peiris M, Wu JT</i><br /><AbstractText>The SARS-CoV-2 Omicron variant has demonstrated enhanced transmissibility and escape of vaccine-derived immunity. While first-generation vaccines remain effective against severe disease and death, robust evidence on vaccine effectiveness (VE) against all Omicron infections, irrespective of symptoms, remains sparse. We used a community-wide serosurvey with 5,310 subjects to estimate how vaccination histories modulated risk of infection in infection-naïve Hong Kong during a large wave of Omicron BA.2 epidemic in January-July 2022. We estimated that Omicron infected 45% (41-48%) of the local population. Three and four doses of BNT162b2 or CoronaVac were effective against Omicron infection (VE of 48% (95% credible interval 34-64%) and 69% (46-98%) for three and four doses of BNT162b2 respectively; VE of 30% (1-66%) and 56% (6-97%) for three and four doses of CoronaVac respectively) seven days after vaccination. 100 days after immunization, VE waned to 26% (7-41%) and 35% (10-71%) for three and four doses of BNT162b2, and to 6% (0-29%) and 11% (0-54%) for three and four doses of CoronaVac. The rapid waning of VE against infection conferred by first-generation vaccines and an increasingly complex viral evolutionary landscape highlights the necessity for rapidly deploying updated vaccines followed by vigilant monitoring of VE.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 18 Jan 2023; epub ahead of print</small></div>
Lau JJ, Cheng SMS, Leung K, Lee CK, ... Peiris M, Wu JT
Nat Med: 18 Jan 2023; epub ahead of print | PMID: 36652990
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<div><h4>[C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.</h4><i>Wu X, Senanayake R, Goodchild E, Bashari WA, ... Drake WM, Brown MJ</i><br /><AbstractText>Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [<sup>11</sup>C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 16 Jan 2023; epub ahead of print</small></div>
Wu X, Senanayake R, Goodchild E, Bashari WA, ... Drake WM, Brown MJ
Nat Med: 16 Jan 2023; epub ahead of print | PMID: 36646800
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<div><h4>Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer.</h4><i>Kotani D, Oki E, Nakamura Y, Yukami H, ... Mori M, Yoshino T</i><br /><AbstractText>Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II-IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49-24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Jan 2023; epub ahead of print</small></div>
Kotani D, Oki E, Nakamura Y, Yukami H, ... Mori M, Yoshino T
Nat Med: 16 Jan 2023; epub ahead of print | PMID: 36646802
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<div><h4>The next generation of evidence-based medicine.</h4><i>Subbiah V</i><br /><AbstractText>Recently, advances in wearable technologies, data science and machine learning have begun to transform evidence-based medicine, offering a tantalizing glimpse into a future of next-generation \'deep\' medicine. Despite stunning advances in basic science and technology, clinical translations in major areas of medicine are lagging. While the COVID-19 pandemic exposed inherent systemic limitations of the clinical trial landscape, it also spurred some positive changes, including new trial designs and a shift toward a more patient-centric and intuitive evidence-generation system. In this Perspective, I share my heuristic vision of the future of clinical trials and evidence-based medicine.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 16 Jan 2023; epub ahead of print</small></div>
Subbiah V
Nat Med: 16 Jan 2023; epub ahead of print | PMID: 36646803
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<div><h4>Machine learning identifies long COVID patterns from electronic health records.</h4><i></i><br /><AbstractText>A machine learning algorithm identifies four reproducible clinical subphenotypes of long COVID from the electronic health records of patients with post-acute sequelae of SARS-CoV-2 infection within 30–180 days of infection; these patterns have implications for the treatment and management of long COVID.</AbstractText><br /><br /><br /><br /><small>Nat Med: 13 Jan 2023:1-2; epub ahead of print</small></div>
Nat Med: 13 Jan 2023:1-2; epub ahead of print | PMID: 36639563
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<div><h4>Estimating the transmission dynamics of SARS-CoV-2 Omicron BF.7 in Beijing after the adjustment of zero-COVID policy in November - December 2022.</h4><i>Leung K, Lau EHY, Wong CKH, Leung GM, Wu JT</i><br /><AbstractText>We tracked the effective reproduction number R<sub>t</sub> of the predominant SARS-CoV-2 variant Omicron BF.7 in Beijing in November - December 2022 by fitting a transmission dynamic model parameterized with real-time mobility data to (i) the daily number of new symptomatic cases on November 1-11 (when China\'s zero-COVID interventions were still strictly enforced) and (ii) the proportion of individuals who participated in online polls on December 10-22 and self-reported to have been test-positive since November 1. After China\'s announcement of \'20 measures\' to transition from zero-COVID, we estimated that R<sub>t</sub> increased to 3.44 (95% CrI: 2.82-4.14) on November 18 and the infection incidence peaked on December 11. We estimated that the cumulative infection attack rate (that is the proportion of population who have been infected since November 1) in Beijing was 75.7% (95% CrI: 60.7-84.4) on December 22, 2022, and 92.3% (95% CrI: 91.4-93.1) on January 31, 2023. Surveillance programmes should be rapidly set up to monitor the evolving epidemiology and evolution of SARS-CoV-2 across China.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 13 Jan 2023; epub ahead of print</small></div>
Leung K, Lau EHY, Wong CKH, Leung GM, Wu JT
Nat Med: 13 Jan 2023; epub ahead of print | PMID: 36638825
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<div><h4>Fully automated closed-loop insulin delivery in adults with type 2 diabetes: an open-label, single-center, randomized crossover trial.</h4><i>Daly AB, Boughton CK, Nwokolo M, Hartnell S, ... Evans ML, Hovorka R</i><br /><AbstractText>In adults with type 2 diabetes, the benefits of fully closed-loop insulin delivery, which does not require meal bolusing, are unclear. In an open-label, single-center, randomized crossover study, 26 adults with type 2 diabetes (7 women and 19 men; (mean ± s.d.) age, 59 ± 11 years; baseline glycated hemoglobin (HbA1c), 75 ± 15 mmol mol<sup>-1</sup> (9.0% ± 1.4%)) underwent two 8-week periods to compare the CamAPS HX fully closed-loop app with standard insulin therapy and a masked glucose sensor (control) in random order, with a 2-week to 4-week washout between periods. The primary endpoint was proportion of time in target glucose range (3.9-10.0 mmol l<sup>-1</sup>). Analysis was by intention to treat. Thirty participants were recruited between 16 December 2020 and 24 November 2021, of whom 28 were randomized to two groups (14 to closed-loop therapy first and 14 to control therapy first). Proportion of time in target glucose range (mean ± s.d.) was 66.3% ± 14.9% with closed-loop therapy versus 32.3% ± 24.7% with control therapy (mean difference, 35.3 percentage points; 95% confidence interval (CI), 28.0-42.6 percentage points; P < 0.001). Time > 10.0 mmol l<sup>-1</sup> was 33.2% ± 14.8% with closed-loop therapy versus 67.0% ± 25.2% with control therapy (mean difference, -35.2 percentage points; 95% CI, -42.8 to -27.5 percentage points; P < 0.001). Mean glucose was lower during the closed-loop therapy period than during the control therapy period (9.2 ± 1.2 mmol l<sup>-1</sup> versus 12.6 ± 3.0 mmol l<sup>-1</sup>, respectively; mean difference, -3.6 mmol l<sup>-1</sup>; 95% CI, -4.6 to -2.5 mmol l<sup>-1</sup>; P < 0.001). HbA1c was lower following closed-loop therapy (57 ± 9 mmol mol<sup>-1</sup> (7.3% ± 0.8%)) than following control therapy (72 ± 13 mmol mol<sup>-1</sup> (8.7% ± 1.2%); mean difference, -15 mmol mol<sup>-1</sup>; 95% CI, -11 to -20 mmol l<sup>-1</sup> (mean difference, -1.4%; 95% CI, -1.0 to -1.8%); P < 0.001). Time < 3.9 mmol l<sup>-1</sup> was similar between treatments (a median of 0.44% (interquartile range, 0.19-0.81%) during the closed-loop therapy period versus a median of 0.08% (interquartile range, 0.00-1.05%) during the control therapy period; P = 0.43). No severe hypoglycemia events occurred in either period. One treatment-related serious adverse event occurred during the closed-loop therapy period. Fully closed-loop insulin delivery improved glucose control without increasing hypoglycemia compared with standard insulin therapy and may represent a safe and efficacious method to improve outcomes in adults with type 2 diabetes. This study is registered with ClinicalTrials.gov (NCT04701424).</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 11 Jan 2023; epub ahead of print</small></div>
Daly AB, Boughton CK, Nwokolo M, Hartnell S, ... Evans ML, Hovorka R
Nat Med: 11 Jan 2023; epub ahead of print | PMID: 36631592
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<div><h4>Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.</h4><i>Genchi A, Brambilla E, Sangalli F, Radaelli M, ... Gaipa G, Martino G</i><br /><AbstractText>Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 09 Jan 2023; epub ahead of print</small></div>
Genchi A, Brambilla E, Sangalli F, Radaelli M, ... Gaipa G, Martino G
Nat Med: 09 Jan 2023; epub ahead of print | PMID: 36624312
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<div><h4>Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.</h4><i>Parry EM, Leshchiner I, Guièze R, Johnson C, ... Getz G, Wu CJ</i><br /><AbstractText>Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 09 Jan 2023; epub ahead of print</small></div>
Parry EM, Leshchiner I, Guièze R, Johnson C, ... Getz G, Wu CJ
Nat Med: 09 Jan 2023; epub ahead of print | PMID: 36624313
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<div><h4>Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer.</h4><i>Foersch S, Glasner C, Woerl AC, Eckstein M, ... Kather JN, Jesinghaus M</i><br /><AbstractText>Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM\'s decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 09 Jan 2023; epub ahead of print</small></div>
Foersch S, Glasner C, Woerl AC, Eckstein M, ... Kather JN, Jesinghaus M
Nat Med: 09 Jan 2023; epub ahead of print | PMID: 36624314
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<div><h4>Autologous T cell therapy for MAGE-A4 solid cancers in HLA-A*02 patients: a phase 1 trial.</h4><i>Hong DS, Van Tine BA, Biswas S, McAlpine C, ... Odunsi K, Butler MO</i><br /><AbstractText>Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 09 Jan 2023; epub ahead of print</small></div>
Hong DS, Van Tine BA, Biswas S, McAlpine C, ... Odunsi K, Butler MO
Nat Med: 09 Jan 2023; epub ahead of print | PMID: 36624315
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<div><h4>A survey of COVID-19 vaccine acceptance across 23 countries in 2022.</h4><i>Lazarus JV, Wyka K, White TM, Picchio CA, ... Kamarulzaman A, El-Mohandes A</i><br /><AbstractText>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continued to mutate and spread in 2022 despite the introduction of safe, effective vaccines and medications. Vaccine hesitancy remains substantial, fueled in part by misinformation. Our third study of Coronavirus Disease 2019 (COVID-19) vaccine hesitancy among 23,000 respondents in 23 countries (Brazil, Canada, China, Ecuador, France, Germany, Ghana, India, Italy, Kenya, Mexico, Nigeria, Peru, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Turkey, the United Kingdom and the United States), surveyed from 29 June to 10 July 2022, found willingness to accept vaccination at 79.1%, up 5.2% from June 2021. Hesitancy increased in eight countries, however, ranging from 1.0% (United Kingdom) to 21.1% (South Africa). Almost one in eight (12.1%) vaccinated respondents are hesitant about booster doses. Overall support for vaccinating children under 18 years of age increased slightly but declined among parents who were personally hesitant. Almost two in five (38.6%) respondents reported paying less attention to new COVID-19 information than previously, and support for vaccination mandates decreased. Almost a quarter (24%) of those who became ill reported taking medications to combat COVID-19 symptoms. Vaccination remains a cornerstone of the COVID-19 pandemic response, but broad public support remains elusive. These data can be used by health system decisionmakers, practitioners, advocates and researchers to address COVID-19 vaccine hesitancy more effectively.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 09 Jan 2023; epub ahead of print</small></div>
Lazarus JV, Wyka K, White TM, Picchio CA, ... Kamarulzaman A, El-Mohandes A
Nat Med: 09 Jan 2023; epub ahead of print | PMID: 36624316
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<div><h4>Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.</h4><i>Lee SHR, Yang W, Gocho Y, John A, ... Evans WE, Yang JJ</i><br /><AbstractText>Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 05 Jan 2023; epub ahead of print</small></div>
Lee SHR, Yang W, Gocho Y, John A, ... Evans WE, Yang JJ
Nat Med: 05 Jan 2023; epub ahead of print | PMID: 36604538
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<div><h4>T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection.</h4><i>Musvosvi M, Huang H, Wang C, Xia Q, ... Adolescent Cohort Study team, GC6-74 Consortium</i><br /><AbstractText>Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two longitudinal cohorts, comprising 166 individuals with M. tuberculosis infection who progressed to either tuberculosis (n = 48) or controlled infection (n = 118). We found 24 T cell groups with similar TCR-β sequences, predicted by GLIPH2 to have common TCR specificities, which were associated with control of infection (n = 17), and others that were associated with progression to disease (n = 7). Using a genome-wide M. tuberculosis antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or in progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 05 Jan 2023; epub ahead of print</small></div>
Musvosvi M, Huang H, Wang C, Xia Q, ... Adolescent Cohort Study team, GC6-74 Consortium
Nat Med: 05 Jan 2023; epub ahead of print | PMID: 36604540
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<div><h4>Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave.</h4><i>Tan ST, Kwan AT, Rodríguez-Barraquer I, Singer BJ, ... Sears D, Lo NC</i><br /><AbstractText>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections in vaccinated individuals and reinfections in previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of individuals with SARS-CoV-2 infections, especially in high-risk populations with intense transmission, such as in prisons. Here we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting. Analyzing SARS-CoV-2 surveillance data from December 2021 to May 2022 across 35 California state prisons with a predominately male population, we estimate that unvaccinated Omicron cases had a 36% (95% confidence interval (CI): 31-42%) risk of transmitting infection to close contacts, as compared to a 28% (25-31%) risk among vaccinated cases. In adjusted analyses, we estimated that any vaccination, prior infection alone and both vaccination and prior infection reduced an index case\'s risk of transmitting infection by 22% (6-36%), 23% (3-39%) and 40% (20-55%), respectively. Receipt of booster doses and more recent vaccination further reduced infectiousness among vaccinated cases. These findings suggest that, although vaccinated and/or previously infected individuals remain highly infectious upon SARS-CoV-2 infection in this prison setting, their infectiousness is reduced compared to individuals without any history of vaccination or infection. This study underscores benefit of vaccination to reduce, but not eliminate, transmission.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 02 Jan 2023; epub ahead of print</small></div>
Tan ST, Kwan AT, Rodríguez-Barraquer I, Singer BJ, ... Sears D, Lo NC
Nat Med: 02 Jan 2023; epub ahead of print | PMID: 36593393
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<div><h4>Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.</h4><i>He Y, Brouwers B, Liu H, Liu H, ... Xu Y, Sadaf Farooqi I</i><br /><AbstractText>Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT<sub>2C</sub>R) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT<sub>2C</sub>R (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT<sub>2C</sub>R agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT<sub>2C</sub>R is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 19 Dec 2022; epub ahead of print</small></div>
He Y, Brouwers B, Liu H, Liu H, ... Xu Y, Sadaf Farooqi I
Nat Med: 19 Dec 2022; epub ahead of print | PMID: 36536256
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<div><h4>IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma.</h4><i>Taylor CA, Watson RA, Tong O, Ye W, ... Gusev A, Fairfax BP</i><br /><AbstractText>Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8<sup>+</sup> T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 16 Dec 2022; epub ahead of print</small></div>
Taylor CA, Watson RA, Tong O, Ye W, ... Gusev A, Fairfax BP
Nat Med: 16 Dec 2022; epub ahead of print | PMID: 36526722
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<div><h4>Germline variants associated with toxicity to immune checkpoint blockade.</h4><i>Groha S, Alaiwi SA, Xu W, Naranbhai V, ... Choueiri TK, Gusev A</i><br /><AbstractText>Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10<sup>-8</sup>) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10<sup>-11</sup>; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10<sup>-8</sup>; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10<sup>-8</sup>, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 16 Dec 2022; epub ahead of print</small></div>
Groha S, Alaiwi SA, Xu W, Naranbhai V, ... Choueiri TK, Gusev A
Nat Med: 16 Dec 2022; epub ahead of print | PMID: 36526723
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<div><h4>Leukocyte telomere length in children born following blastocyst-stage embryo transfer.</h4><i>Wang C, Gu Y, Zhou J, Zang J, ... Shen H, Hu Z</i><br /><AbstractText>Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10<sup>-3</sup>) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10<sup>-3</sup>) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10<sup>-4</sup>) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 15 Dec 2022; epub ahead of print</small></div>
Wang C, Gu Y, Zhou J, Zang J, ... Shen H, Hu Z
Nat Med: 15 Dec 2022; epub ahead of print | PMID: 36522605
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<div><h4>Dapagliflozin in heart failure with improved ejection fraction: a prespecified analysis of the DELIVER trial.</h4><i>Vardeny O, Fang JC, Desai AS, Jhund PS, ... McMurray JJV, Solomon SD</i><br /><AbstractText>With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial ( NCT03619213 ), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF >40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to >40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently >40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56-0.97), first worsening heart failure events (HR = 0.78, 95% CI = 0.61-1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41-0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50-0.94) to a similar extent as for individuals with an EF consistently >40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 15 Dec 2022; epub ahead of print</small></div>
Vardeny O, Fang JC, Desai AS, Jhund PS, ... McMurray JJV, Solomon SD
Nat Med: 15 Dec 2022; epub ahead of print | PMID: 36522606
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<div><h4>Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.</h4><i>Thompson RC, Simons NW, Wilkins L, Cheng E, ... Charney AW, Beckmann ND</i><br /><AbstractText>Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 08 Dec 2022; epub ahead of print</small></div>
Thompson RC, Simons NW, Wilkins L, Cheng E, ... Charney AW, Beckmann ND
Nat Med: 08 Dec 2022; epub ahead of print | PMID: 36482101
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<div><h4>Impact of the Human Cell Atlas on medicine.</h4><i>Rood JE, Maartens A, Hupalowska A, Teichmann SA, Regev A</i><br /><AbstractText>Single-cell atlases promise to provide a \'missing link\' between genes, diseases and therapies. By identifying the specific cell types, states, programs and contexts where disease-implicated genes act, we will understand the mechanisms of disease at the cellular and tissue levels and can use this understanding to develop powerful disease diagnostics; identify promising new drug targets; predict their efficacy, toxicity and resistance mechanisms; and empower new kinds of therapies, from cancer therapies to regenerative medicine. Here, we lay out a vision for the potential of cell atlases to impact the future of medicine, and describe how advances over the past decade have begun to realize this potential in common complex diseases, infectious diseases (including COVID-19), rare diseases and cancer.</AbstractText><br /><br />© 2022. Springer Nature America, Inc.<br /><br /><small>Nat Med: 08 Dec 2022; epub ahead of print</small></div>
Rood JE, Maartens A, Hupalowska A, Teichmann SA, Regev A
Nat Med: 08 Dec 2022; epub ahead of print | PMID: 36482102
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<div><h4>Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial.</h4><i>Røssevold AH, Andresen NK, Bjerre CA, Gilje B, ... Naume B, Kyte JA</i><br /><AbstractText>Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1<sup>positive</sup> disease. The randomized, placebo-controlled ALICE trial ( NCT03164993 , 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33-0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33-0.95; P = 0.033). A numerical advantage was observed for both the PD-L1<sup>positive</sup> (n = 27; HR = 0.65; 95% CI 0.27-1.54) and PD-L1<sup>negative</sup> subgroups (n = 31; HR = 0.57, 95% CI 0.27-1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4-30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 08 Dec 2022; epub ahead of print</small></div>
Røssevold AH, Andresen NK, Bjerre CA, Gilje B, ... Naume B, Kyte JA
Nat Med: 08 Dec 2022; epub ahead of print | PMID: 36482103
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<div><h4>Association of wearable device-measured vigorous intermittent lifestyle physical activity with mortality.</h4><i>Stamatakis E, Ahmadi MN, Gill JMR, Thøgersen-Ntoumani C, ... Doherty A, Hamer M</i><br /><AbstractText>Wearable devices can capture unexplored movement patterns such as brief bursts of vigorous intermittent lifestyle physical activity (VILPA) that is embedded into everyday life, rather than being done as leisure time exercise. Here, we examined the association of VILPA with all-cause, cardiovascular disease (CVD) and cancer mortality in 25,241 nonexercisers (mean age 61.8 years, 14,178 women/11,063 men) in the UK Biobank. Over an average follow-up of 6.9 years, during which 852 deaths occurred, VILPA was inversely associated with all three of these outcomes in a near-linear fashion. Compared with participants who engaged in no VILPA, participants who engaged in VILPA at the sample median VILPA frequency of 3 length-standardized bouts per day (lasting 1 or 2 min each) showed a 38%-40% reduction in all-cause and cancer mortality risk and a 48%-49% reduction in CVD mortality risk. Moreover, the sample median VILPA duration of 4.4 min per day was associated with a 26%-30% reduction in all-cause and cancer mortality risk and a 32%-34% reduction in CVD mortality risk. We obtained similar results when repeating the above analyses for vigorous physical activity (VPA) in 62,344 UK Biobank participants who exercised (1,552 deaths, 35,290 women/27,054 men). These results indicate that small amounts of vigorous nonexercise physical activity are associated with substantially lower mortality. VILPA in nonexercisers appears to elicit similar effects to VPA in exercisers, suggesting that VILPA may be a suitable physical activity target, especially in people not able or willing to exercise.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 08 Dec 2022; epub ahead of print</small></div>
Stamatakis E, Ahmadi MN, Gill JMR, Thøgersen-Ntoumani C, ... Doherty A, Hamer M
Nat Med: 08 Dec 2022; epub ahead of print | PMID: 36482104
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<div><h4>Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study.</h4><i>Shields BM, Dennis JM, Angwin CD, Warren F, ... Hattersley AT, TriMaster Study group</i><br /><AbstractText>Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. In this study, we tested two hypotheses: (1) individuals with body mass index (BMI) > 30 kg/m<sup>2</sup>, compared to BMI ≤ 30 kg/m<sup>2</sup>, have greater glucose lowering with thiazolidinediones than with DPP4 inhibitors, and (2) individuals with estimated glomerular filtration rate (eGFR) 60-90 ml/min/1.73 m<sup>2</sup>, compared to eGFR >90 ml/min/1.73 m<sup>2</sup>, have greater glucose lowering with DPP4 inhibitors than with SGLT2 inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. In total, 525 people with type 2 diabetes participated in this UK-based randomized, double-blind, three-way crossover trial of 16 weeks of treatment with each of sitagliptin 100 mg once daily, canagliflozin 100 mg once daily and pioglitazone 30 mg once daily added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs: pioglitazone 59.6 mmol/mol, sitagliptin 60.0 mmol/mol and canagliflozin 60.6 mmol/mol (P = 0.2). Participants with BMI > 30 kg/m<sup>2</sup>, compared to BMI ≤ 30 kg/m<sup>2</sup>, had a 2.88 mmol/mol (95% confidence interval (CI): 0.98, 4.79) lower HbA1c on pioglitazone than on sitagliptin (n = 356, P = 0.003). Participants with eGFR 60-90 ml/min/1.73 m<sup>2</sup>, compared to eGFR >90 ml/min/1.73 m<sup>2</sup>, had a 2.90 mmol/mol (95% CI: 1.19, 4.61) lower HbA1c on sitagliptin than on canagliflozin (n = 342, P = 0.001). There were 2,201 adverse events reported, and 447/525 (85%) randomized participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple, routinely available clinical measures to identify the drug class most likely to deliver the greatest glycemic reduction for a given patient. (ClinicalTrials.gov registration: NCT02653209 ; ISRCTN registration: 12039221 .).</AbstractText><br /><br />© 2022. The Author(s) under exclusive license to Springer Nature America, Inc.<br /><br /><small>Nat Med: 07 Dec 2022; epub ahead of print</small></div>
Shields BM, Dennis JM, Angwin CD, Warren F, ... Hattersley AT, TriMaster Study group
Nat Med: 07 Dec 2022; epub ahead of print | PMID: 36477733
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<div><h4>Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study.</h4><i>Shields BM, Angwin CD, Shepherd MH, Britten N, ... Pearson ER, Hattersley AT</i><br /><AbstractText>Patient preference is very important for medication selection in chronic medical conditions, like type 2 diabetes, where there are many different drugs available. Patient preference balances potential efficacy with potential side effects. As both aspects of drug response can vary markedly between individuals, this decision could be informed by the patient personally experiencing the alternative medications, as occurs in a crossover trial. In the TriMaster (NCT02653209, ISRCTN12039221), randomized double-blind, three-way crossover trial patients received three different second- or third-line once-daily type 2 diabetes glucose-lowering drugs (pioglitazone 30 mg, sitagliptin 100 mg and canagliflozin 100 mg). As part of a prespecified secondary endpoint, we examined patients\' drug preference after they had tried all three drugs. In total, 448 participants were treated with all three drugs which overall showed similar glycemic control (HbA1c on pioglitazone 59.5 sitagliptin 59.9, canagliflozin 60.5 mmol mol<sup>-1</sup>, P = 0.19). In total, 115 patients (25%) preferred pioglitazone, 158 patients (35%) sitagliptin and 175 patients (38%) canagliflozin. The drug preferred by individual patients was associated with a lower HbA1c (mean: 4.6; 95% CI: 3.9, 5.3) mmol mol<sup>-1</sup> lower versus nonpreferred) and fewer side effects (mean: 0.50; 95% CI: 0.35, 0.64) fewer side effects versus nonpreferred). Allocating therapy based on the individually preferred drugs, rather than allocating all patients the overall most preferred drug (canagliflozin), would result in more patients achieving the lowest HbA1c for them (70% versus 30%) and the fewest side effects (67% versus 50%). When precision approaches do not predict a clear optimal therapy for an individual, allowing patients to try potential suitable medications before they choose long-term therapy could be a practical alternative to optimizing treatment for type 2 diabetes.</AbstractText><br /><br />© 2022. The Author(s) under exclusive license to Springer Nature America, Inc.<br /><br /><small>Nat Med: 07 Dec 2022; epub ahead of print</small></div>
Shields BM, Angwin CD, Shepherd MH, Britten N, ... Pearson ER, Hattersley AT
Nat Med: 07 Dec 2022; epub ahead of print | PMID: 36477734
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<div><h4>Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by parental mRNA vaccine or a BA.5-bivalent booster.</h4><i>Kurhade C, Zou J, Xia H, Liu M, ... Xie X, Shi PY</i><br /><AbstractText>The newly emerged SARS-CoV-2 Omicron sublineages, including the BA.2-derived BA.2.75.2 and the BA.5-derived BQ.1.1 and XBB.1, have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 23-94 days after dose 4 of a parental mRNA vaccine, 14-32 days after a BA.5-bivalent-booster from individuals with 2-4 previous doses of parental mRNA vaccine, or 15-32 days after a BA.5-bivalent-booster from individuals with previous SARS-CoV-2 infection and 2-4 doses of parental mRNA vaccine. The results showed that a BA.5-bivalent-booster elicited a high neutralizing titer against BA.4/5 measured at 14- to 32-day post-boost; however, the BA.5-bivalent-booster did not produce robust neutralization against the newly emerged BA.2.75.2, BQ.1.1, or XBB.1. Previous infection significantly enhanced the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization. Our data support a vaccine update strategy that future boosters should match newly emerged circulating SARS-CoV-2 variants.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 06 Dec 2022; epub ahead of print</small></div>
Kurhade C, Zou J, Xia H, Liu M, ... Xie X, Shi PY
Nat Med: 06 Dec 2022; epub ahead of print | PMID: 36473500
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<div><h4>Whole-body CD8 T cell visualization before and during cancer immunotherapy: a phase 1/2 trial.</h4><i>Kist de Ruijter L, van de Donk PP, Hooiveld-Noeken JS, Giesen D, ... de Groot DJA, de Vries EGE</i><br /><AbstractText>Immune checkpoint inhibitors (ICIs), by reinvigorating CD8<sup>+</sup> T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8<sup>+</sup> T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer <sup>89</sup>ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed <sup>89</sup>ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUV<sub>max</sub>) 5.2, IQI 4.0-7.4). Higher SUV<sub>max</sub> was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8<sup>+</sup> T cell distribution and pharmacodynamics within and between patients. In conclusion, <sup>89</sup>ZED88082A can characterize the complex dynamics of CD8<sup>+</sup> T cells in the context of ICIs, and may inform immunotherapeutic treatments.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 05 Dec 2022; epub ahead of print</small></div>
Kist de Ruijter L, van de Donk PP, Hooiveld-Noeken JS, Giesen D, ... de Groot DJA, de Vries EGE
Nat Med: 05 Dec 2022; epub ahead of print | PMID: 36471036
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<div><h4>Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.</h4><i>Anker SD, Butler J, Usman MS, Filippatos G, ... Pocock SJ, Zannad F</i><br /><AbstractText>The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF)  > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF  ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (P<sub>interaction</sub> = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (P<sub>interaction</sub> = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 05 Dec 2022; epub ahead of print</small></div>
Anker SD, Butler J, Usman MS, Filippatos G, ... Pocock SJ, Zannad F
Nat Med: 05 Dec 2022; epub ahead of print | PMID: 36471037
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<div><h4>Efficacy of supermarket and web-based interventions for improving dietary quality: a randomized, controlled trial.</h4><i>Steen DL, Helsley RN, Bhatt DL, King EC, ... Eckman MH, Couch SC</i><br /><AbstractText>Dietary interventions may best be delivered at supermarkets, which offer convenience, accessibility, full food inventories and, increasingly, in-store registered dietitians, online shopping and delivery services. In collaboration with a large retail supermarket chain, we conducted a multisite supermarket and web-based intervention targeting nutrition trial (no. NCT03895580), randomizing participants (n = 247 (139 women and 108 men)) 2:2:1 to two levels of dietary education (Strategy 1 and Strategy 2) or an enhanced control group that included educational components beyond the routine standard of care. Both Strategies 1 and 2 included individualized, in-person, dietitian-led, purchasing data-guided interventions. Strategy 2 also included online tools for shopping, home delivery, selection of healthier purchases, meal planning and healthy recipes. The primary endpoint was change in dietary approaches to stop hypertension (DASH) score (a measure of adherence to the DASH diet) from baseline to 3 months. The primary endpoint was met because, at 3 months, the DASH score increased by 4.7 more for the combined Strategy 1 and Strategy 2 groups than for the control group (95% confidence interval (CI) (0.9, 8.5), P = 0.02). In a prespecified hierarchical test, at 3 months, DASH score increased by 3.8 more for the Strategy 2 group than for the Strategy 1 group (95% CI (0.8, 6.)9, P = 0.01). This trial demonstrates the efficacy of data-guided, supermarket-based, dietary interventions and modern online shopping tools in improving dietary quality in a free-living, community-based population. The trial also demonstrates the opportunity for academic investigators to collaborate with retailers to design and rigorously test comprehensive healthcare interventions.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 01 Dec 2022; epub ahead of print</small></div>
Steen DL, Helsley RN, Bhatt DL, King EC, ... Eckman MH, Couch SC
Nat Med: 01 Dec 2022; epub ahead of print | PMID: 36456831
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<div><h4>Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer\'s trial selection and disease monitoring.</h4><i>Ashton NJ, Janelidze S, Mattsson-Carlgren N, Binette AP, ... Blennow K, Hansson O</i><br /><AbstractText>Blood biomarkers indicative of Alzheimer\'s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer\'s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 01 Dec 2022; epub ahead of print</small></div>
Ashton NJ, Janelidze S, Mattsson-Carlgren N, Binette AP, ... Blennow K, Hansson O
Nat Med: 01 Dec 2022; epub ahead of print | PMID: 36456833
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<div><h4>Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes.</h4><i>Zhang H, Zang C, Xu Z, Zhang Y, ... Wang F, Kaushal R</i><br /><AbstractText>The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated or newly incident in the period after acute SARS-CoV-2 infection. Most studies have examined these conditions individually without providing evidence on co-occurring conditions. In this study, we leveraged the electronic health record data of two large cohorts, INSIGHT and OneFlorida+, from the national Patient-Centered Clinical Research Network. We created a development cohort from INSIGHT and a validation cohort from OneFlorida+ including 20,881 and 13,724 patients, respectively, who were SARS-CoV-2 infected, and we investigated their newly incident diagnoses 30-180 days after a documented SARS-CoV-2 infection. Through machine learning analysis of over 137 symptoms and conditions, we identified four reproducible PASC subphenotypes, dominated by cardiac and renal (including 33.75% and 25.43% of the patients in the development and validation cohorts); respiratory, sleep and anxiety (32.75% and 38.48%); musculoskeletal and nervous system (23.37% and 23.35%); and digestive and respiratory system (10.14% and 12.74%) sequelae. These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. Our study provides insights into the heterogeneity of PASC and may inform stratified decision-making in the management of PASC conditions.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 01 Dec 2022; epub ahead of print</small></div>
Zhang H, Zang C, Xu Z, Zhang Y, ... Wang F, Kaushal R
Nat Med: 01 Dec 2022; epub ahead of print | PMID: 36456834
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<div><h4>Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial.</h4><i>Gerwin N, Scotti C, Halleux C, Fornaro M, ... Roubenoff R, Kneissel M</i><br /><AbstractText>Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α<sub>5</sub>β<sub>1</sub> on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 01 Dec 2022; epub ahead of print</small></div>
Gerwin N, Scotti C, Halleux C, Fornaro M, ... Roubenoff R, Kneissel M
Nat Med: 01 Dec 2022; epub ahead of print | PMID: 36456835
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<div><h4>Effect of air pollution on the human immune system.</h4><i></i><br /><AbstractText>Inhaled particulates from environmental pollutants accumulate in macrophages in lung-associated lymph nodes over years, compromising immune surveillance via direct effects on immune cell function and lymphoid architecture. These findings reveal the importance of improved air quality to preserve immune health against current and emerging pathogens.</AbstractText><br /><br /><br /><br /><small>Nat Med: 01 Dec 2022; 28:2482-2483</small></div>
Nat Med: 01 Dec 2022; 28:2482-2483 | PMID: 36456836
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<div><h4>CSF tau microtubule-binding region identifies pathological changes in primary tauopathies.</h4><i>Horie K, Barthélemy NR, Spina S, VandeVrede L, ... Bateman RJ, Sato C</i><br /><AbstractText>Despite recent advances in fluid biomarker research in Alzheimer\'s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau<sub>275</sub> and MTBR-tau<sub>282</sub>) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick\'s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau<sub>275</sub> and MTBR-tau<sub>282</sub> may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 24 Nov 2022; epub ahead of print</small></div>
Horie K, Barthélemy NR, Spina S, VandeVrede L, ... Bateman RJ, Sato C
Nat Med: 24 Nov 2022; epub ahead of print | PMID: 36424467
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<div><h4>Inhaled particulate accumulation with age impairs immune function and architecture in human lung lymph nodes.</h4><i>Ural BB, Caron DP, Dogra P, Wells SB, ... Matsumoto R, Farber DL</i><br /><AbstractText>Older people are particularly susceptible to infectious and neoplastic diseases of the lung and it is unclear how lifelong exposure to environmental pollutants affects respiratory immune function. In an analysis of human lymph nodes (LNs) from 84 organ donors aged 11-93 years, we found a specific age-related decline in lung-associated, but not gut-associated, LN immune function linked to the accumulation of inhaled atmospheric particulate matter. Increasing densities of particulates were found in lung-associated LNs with age, but not in the corresponding gut-associated LNs. Particulates were specifically contained within CD68<sup>+</sup>CD169<sup>-</sup> macrophages, which exhibited decreased activation, phagocytic capacity, and altered cytokine production compared with non-particulate-containing macrophages. The structures of B cell follicles and lymphatic drainage were also disrupted in lung-associated LNs with particulates. Our results reveal that the cumulative effects of environmental exposure and age may compromise immune surveillance of the lung via direct effects on immune cell function and lymphoid architecture.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 21 Nov 2022; epub ahead of print</small></div>
Ural BB, Caron DP, Dogra P, Wells SB, ... Matsumoto R, Farber DL
Nat Med: 21 Nov 2022; epub ahead of print | PMID: 36411343
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<div><h4>Global and regional estimates of orphans attributed to maternal cancer mortality in 2020.</h4><i>Guida F, Kidman R, Ferlay J, Schüz J, ... Dos-Santos-Silva I, McCormack V</i><br /><AbstractText>Despite women being disproportionally affected by cancer deaths at young ages, there are no global estimates of the resulting maternal orphans, who experience health and education disadvantages throughout their lives. We estimated the number of children who became maternal orphans in 2020 due to their mother dying from cancer in that year, for 185 countries worldwide and by cause of cancer-related death. Female cancer deaths-by country, cancer type and age (derived from GLOBOCAN estimates)-were multiplied by each woman\'s estimated number of children under the age of 18 years at the time of her death (fertility data were derived from United Nations World Population Prospects for birth cohort), accounting for child mortality and parity-cancer risk associations. Globally, there were 1,047,000 such orphans. Over half of these were orphans due to maternal deaths from breast (258,000, 25%), cervix (210,000, 20%) and upper-gastrointestinal cancers (136,000, 13%), and most occurred in Asia (48%: India 15%, China 10%, rest of Asia 23%) and Africa (35%). Globally, there were 40 new maternal orphans due to cancer per 100,000 children, with a declining trend with a higher Human Development Index (range: 121 in Malawi to 15 in Malta). An estimated 7 million children were prevalent maternal orphans due to cancer in mid-2020. Accelerating the implementation of the World Health Organization\'s cervical and breast cancer initiatives has the potential to avert not only millions of preventable female cancer deaths but also the associated, often-overlooked, intergenerational consequences of these deaths.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 20 Nov 2022; epub ahead of print</small></div>
Guida F, Kidman R, Ferlay J, Schüz J, ... Dos-Santos-Silva I, McCormack V
Nat Med: 20 Nov 2022; epub ahead of print | PMID: 36404355
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<div><h4>Prospective evaluation of smartwatch-enabled detection of left ventricular dysfunction.</h4><i>Attia ZI, Harmon DM, Dugan J, Manka L, ... Leibovich BC, Friedman PA</i><br /><AbstractText>Although artificial intelligence (AI) algorithms have been shown to be capable of identifying cardiac dysfunction, defined as ejection fraction (EF) ≤ 40%, from 12-lead electrocardiograms (ECGs), identification of cardiac dysfunction using the single-lead ECG of a smartwatch has yet to be tested. In the present study, a prospective study in which patients of Mayo Clinic were invited by email to download a Mayo Clinic iPhone application that sends watch ECGs to a secure data platform, we examined patient engagement with the study app and the diagnostic utility of the ECGs. We digitally enrolled 2,454 unique patients (mean age 53 ± 15 years, 56% female) from 46 US states and 11 countries, who sent 125,610 ECGs to the data platform between August 2021 and February 2022; 421 participants had at least one watch-classified sinus rhythm ECG within 30 d of an echocardiogram, of whom 16 (3.8%) had an EF ≤ 40%. The AI algorithm detected patients with low EF with an area under the curve of 0.885 (95% confidence interval 0.823-0.946) and 0.881 (0.815-0.947), using the mean prediction within a 30-d window or the closest ECG relative to the echocardiogram that determined the EF, respectively. These findings indicate that consumer watch ECGs, acquired in nonclinical environments, can be used to identify patients with cardiac dysfunction, a potentially life-threatening and often asymptomatic condition.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 14 Nov 2022; epub ahead of print</small></div>
Attia ZI, Harmon DM, Dugan J, Manka L, ... Leibovich BC, Friedman PA
Nat Med: 14 Nov 2022; epub ahead of print | PMID: 36376461
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Abstract
<div><h4>Rare and common genetic determinants of metabolic individuality and their effects on human health.</h4><i>Surendran P, Stewart ID, Au Yeung VPW, Pietzner M, ... Butterworth AS, Langenberg C</i><br /><AbstractText>Garrod\'s concept of \'chemical individuality\' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10<sup>-11</sup>) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Surendran P, Stewart ID, Au Yeung VPW, Pietzner M, ... Butterworth AS, Langenberg C
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357675
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Abstract
<div><h4>Acute and postacute sequelae associated with SARS-CoV-2 reinfection.</h4><i>Bowe B, Xie Y, Al-Aly Z</i><br /><AbstractText>First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs\' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93-2.45), hospitalization (HR = 3.32, 95% CI 3.13-3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.</AbstractText><br /><br />© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Bowe B, Xie Y, Al-Aly Z
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357676
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Abstract
<div><h4>Proteomic signatures for identification of impaired glucose tolerance.</h4><i>Carrasco-Zanini J, Pietzner M, Lindbohm JV, Wheeler E, ... Wareham NJ, Langenberg C</i><br /><AbstractText>The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Carrasco-Zanini J, Pietzner M, Lindbohm JV, Wheeler E, ... Wareham NJ, Langenberg C
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357677
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<div><h4>Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.</h4><i>Jee J, Lebow ES, Yeh R, Das JP, ... Isbell JM, Li BT</i><br /><AbstractText>Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.</AbstractText><br /><br />© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Jee J, Lebow ES, Yeh R, Das JP, ... Isbell JM, Li BT
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357680
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<div><h4>Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline.</h4><i>Ossenkoppele R, Pichet Binette A, Groot C, Smith R, ... Jack CR, Hansson O</i><br /><AbstractText>A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer\'s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A<sup>+</sup>) and tau PET-positive (T<sup>+</sup>) in the medial temporal lobe (A<sup>+</sup>T<sub>MTL</sub><sup>+</sup>) and/or in the temporal neocortex (A<sup>+</sup>T<sub>NEO-T</sub><sup>+</sup>) and compared them with A<sup>+</sup>T<sup>-</sup> and A<sup>-</sup>T<sup>-</sup> groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A<sup>+</sup>T<sub>NEO-T</sub><sup>+</sup> (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A<sup>+</sup>T<sub>MTL</sub><sup>+</sup> (HR = 14.6, 95% CI = 8.1-26.4) and A<sup>+</sup>T<sup>-</sup> (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A<sup>-</sup>T<sup>-</sup> (reference) group. Both A<sup>+</sup>T<sub>MTL</sub><sup>+</sup> (HR = 6.0, 95% CI = 3.4-10.6) and A<sup>+</sup>T<sub>NEO-T</sub><sup>+</sup> (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A<sup>+</sup>T<sup>-</sup> group. Linear mixed-effect models indicated that the A<sup>+</sup>T<sub>NEO-T</sub><sup>+</sup> (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A<sup>+</sup>T<sub>MTL</sub><sup>+</sup> (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A<sup>+</sup>T<sup>-</sup> (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A<sup>-</sup>T<sup>-</sup> (reference) group (all P < 0.001). Both A<sup>+</sup>T<sub>NEO-T</sub><sup>+</sup> (P < 0.001) and A<sup>+</sup>T<sub>MTL</sub><sup>+</sup> (P = 0.002) groups also progressed faster than the A<sup>+</sup>T<sup>-</sup> group. In summary, evidence of advanced Alzheimer\'s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.</AbstractText><br /><br />© 2022. The Author(s).<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Ossenkoppele R, Pichet Binette A, Groot C, Smith R, ... Jack CR, Hansson O
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357681
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<div><h4>The landscape of mRNA nanomedicine.</h4><i>Huang X, Kong N, Zhang X, Cao Y, Langer R, Tao W</i><br /><AbstractText>Messenger RNA (mRNA) is an emerging class of therapeutic agent for the prevention and treatment of a wide range of diseases. The recent success of the two highly efficacious mRNA vaccines produced by Moderna and Pfizer-BioNTech to protect against COVID-19 highlights the huge potential of mRNA technology for revolutionizing life science and medical research. Challenges related to mRNA stability and immunogenicity, as well as in vivo delivery and the ability to cross multiple biological barriers, have been largely addressed by recent progress in mRNA engineering and delivery. In this Review, we present the latest advances and innovations in the growing field of mRNA nanomedicine, in the context of ongoing clinical translation and future directions to improve clinical efficacy.</AbstractText><br /><br />© 2022. Springer Nature America, Inc.<br /><br /><small>Nat Med: 10 Nov 2022; epub ahead of print</small></div>
Huang X, Kong N, Zhang X, Cao Y, Langer R, Tao W
Nat Med: 10 Nov 2022; epub ahead of print | PMID: 36357682
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Abstract
<div><h4>Long-term neurological sequelae of SARS-CoV-2 infection.</h4><i></i><br /><AbstractText>We show that patients who survive the first 30 days of acute SARS-CoV-2 infection have an increased risk of various post-acute neurological disorders after 1 year compared with uninfected contemporaries. The burden of these sequelae (aspects of ‘long COVID’) has serious implications for patients as well as society.</AbstractText><br /><br /><br /><br /><small>Nat Med: 01 Nov 2022; 28:2269-2270</small></div>
Nat Med: 01 Nov 2022; 28:2269-2270 | PMID: 36192556
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<div><h4>Quantifying the effect of inequitable global vaccine coverage on the COVID-19 pandemic.</h4><i></i><br /><AbstractText>We used a global mathematical model simulating different scenarios to study the effects of increased COVID-19 vaccine equity during 2021. Our results indicate that vaccine nationalism leads to increased infections and mortality worldwide, and by favoring the emergence of new viral variants, in the long term it may adversely affect all countries.</AbstractText><br /><br /><br /><br /><small>Nat Med: 01 Nov 2022; 28:2271-2272</small></div>
Nat Med: 01 Nov 2022; 28:2271-2272 | PMID: 36333402
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