Journal: Nat Med

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Abstract

Metabolomic profiles predict individual multidisease outcomes.

Buergel T, Steinfeldt J, Ruyoga G, Pietzner M, ... Eils R, Landmesser U
Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.

© 2022. The Author(s).

Nat Med: 22 Sep 2022; epub ahead of print
Buergel T, Steinfeldt J, Ruyoga G, Pietzner M, ... Eils R, Landmesser U
Nat Med: 22 Sep 2022; epub ahead of print | PMID: 36138150
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Abstract

Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome.

Simpson RC, Shanahan ER, Batten M, Reijers ILM, ... Scolyer RA, Long GV
The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes than in Bacteroidaceae-dominated microbiomes. Poor response was associated with lower fiber and omega 3 fatty acid consumption and elevated levels of C-reactive protein in the peripheral circulation at baseline. Together, these data provide insight into the relevance of native gut microbiota signatures, dietary intake and systemic inflammation in shaping the response to and toxicity from ICIs, prompting the need for further studies in this area.

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

Nat Med: 22 Sep 2022; epub ahead of print
Simpson RC, Shanahan ER, Batten M, Reijers ILM, ... Scolyer RA, Long GV
Nat Med: 22 Sep 2022; epub ahead of print | PMID: 36138151
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Abstract

A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma.

Bachy E, Le Gouill S, Di Blasi R, Sesques P, ... Houot R, Morschhauser F
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.

© 2022. The Author(s).

Nat Med: 22 Sep 2022; epub ahead of print
Bachy E, Le Gouill S, Di Blasi R, Sesques P, ... Houot R, Morschhauser F
Nat Med: 22 Sep 2022; epub ahead of print | PMID: 36138152
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Abstract

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, ... Boxer AL, Frontotemporal Dementia Prevention Initiative (FPI) Investigators
Unlike familial Alzheimer\'s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

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

Nat Med: 22 Sep 2022; epub ahead of print
Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, ... Boxer AL, Frontotemporal Dementia Prevention Initiative (FPI) Investigators
Nat Med: 22 Sep 2022; epub ahead of print | PMID: 36138153
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Abstract

Long-term neurologic outcomes of COVID-19.

Xu E, Xie Y, Al-Aly Z
The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

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

Nat Med: 22 Sep 2022; epub ahead of print
Xu E, Xie Y, Al-Aly Z
Nat Med: 22 Sep 2022; epub ahead of print | PMID: 36138154
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Abstract

Multimodal biomedical AI.

Acosta JN, Falcone GJ, Rajpurkar P, Topol EJ
The increasing availability of biomedical data from large biobanks, electronic health records, medical imaging, wearable and ambient biosensors, and the lower cost of genome and microbiome sequencing have set the stage for the development of multimodal artificial intelligence solutions that capture the complexity of human health and disease. In this Review, we outline the key applications enabled, along with the technical and analytical challenges. We explore opportunities in personalized medicine, digital clinical trials, remote monitoring and care, pandemic surveillance, digital twin technology and virtual health assistants. Further, we survey the data, modeling and privacy challenges that must be overcome to realize the full potential of multimodal artificial intelligence in health.

© 2022. Springer Nature America, Inc.

Nat Med: 15 Sep 2022; epub ahead of print
Acosta JN, Falcone GJ, Rajpurkar P, Topol EJ
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109635
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Abstract

Drivers and determinants of strain dynamics following fecal microbiota transplantation.

Schmidt TSB, Li SS, Maistrenko OM, Akanni W, ... Nieuwdorp M, Bork P
Fecal microbiota transplantation (FMT) is a therapeutic intervention for inflammatory diseases of the gastrointestinal tract, but its clinical mode of action and subsequent microbiome dynamics remain poorly understood. Here we analyzed metagenomes from 316 FMTs, sampled pre and post intervention, for the treatment of ten different disease indications. We quantified strain-level dynamics of 1,089 microbial species, complemented by 47,548 newly constructed metagenome-assembled genomes. Donor strain colonization and recipient strain resilience were mostly independent of clinical outcomes, but accurately predictable using LASSO-regularized regression models that accounted for host, microbiome and procedural variables. Recipient factors and donor-recipient complementarity, encompassing entire microbial communities to individual strains, were the main determinants of strain population dynamics, providing insights into the underlying processes that shape the post-FMT gut microbiome. Applying an ecology-based framework to our findings indicated parameters that may inform the development of more effective, targeted microbiome therapies in the future, and suggested how patient stratification can be used to enhance donor microbiota colonization or the displacement of recipient microbes in clinical practice.

© 2022. The Author(s).

Nat Med: 15 Sep 2022; epub ahead of print
Schmidt TSB, Li SS, Maistrenko OM, Akanni W, ... Nieuwdorp M, Bork P
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109636
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Abstract

Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases.

Ianiro G, Punčochář M, Karcher N, Porcari S, ... Cammarota G, Segata N
Fecal microbiota transplantation (FMT) is highly effective against recurrent Clostridioides difficile infection and is considered a promising treatment for other microbiome-related disorders, but a comprehensive understanding of microbial engraftment dynamics is lacking, which prevents informed applications of this therapeutic approach. Here, we performed an integrated shotgun metagenomic systematic meta-analysis of new and publicly available stool microbiomes collected from 226 triads of donors, pre-FMT recipients and post-FMT recipients across eight different disease types. By leveraging improved metagenomic strain-profiling to infer strain sharing, we found that recipients with higher donor strain engraftment were more likely to experience clinical success after FMT (P = 0.017) when evaluated across studies. Considering all cohorts, increased engraftment was noted in individuals receiving FMT from multiple routes (for example, both via capsules and colonoscopy during the same treatment) as well as in antibiotic-treated recipients with infectious diseases compared with antibiotic-naïve patients with noncommunicable diseases. Bacteroidetes and Actinobacteria species (including Bifidobacteria) displayed higher engraftment than Firmicutes except for six under-characterized Firmicutes species. Cross-dataset machine learning predicted the presence or absence of species in the post-FMT recipient at 0.77 average AUROC in leave-one-dataset-out evaluation, and highlighted the relevance of microbial abundance, prevalence and taxonomy to infer post-FMT species presence. By exploring the dynamics of microbiome engraftment after FMT and their association with clinical variables, our study uncovered species-specific engraftment patterns and presented machine learning models able to predict donors that might optimize post-FMT specific microbiome characteristics for disease-targeted FMT protocols.

© 2022. The Author(s).

Nat Med: 15 Sep 2022; epub ahead of print
Ianiro G, Punčochář M, Karcher N, Porcari S, ... Cammarota G, Segata N
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109637
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Abstract

A digital mask to safeguard patient privacy.

Yang Y, Lyu J, Wang R, Wen Q, ... Dai Q, Lin H
The storage of facial images in medical records poses privacy risks due to the sensitive nature of the personal biometric information that can be extracted from such images. To minimize these risks, we developed a new technology, called the digital mask (DM), which is based on three-dimensional reconstruction and deep-learning algorithms to irreversibly erase identifiable features, while retaining disease-relevant features needed for diagnosis. In a prospective clinical study to evaluate the technology for diagnosis of ocular conditions, we found very high diagnostic consistency between the use of original and reconstructed facial videos (κ ≥ 0.845 for strabismus, ptosis and nystagmus, and κ = 0.801 for thyroid-associated orbitopathy) and comparable diagnostic accuracy (P ≥ 0.131 for all ocular conditions tested) was observed. Identity removal validation using multiple-choice questions showed that compared to image cropping, the DM could much more effectively remove identity attributes from facial images. We further confirmed the ability of the DM to evade recognition systems using artificial intelligence-powered re-identification algorithms. Moreover, use of the DM increased the willingness of patients with ocular conditions to provide their facial images as health information during medical treatment. These results indicate the potential of the DM algorithm to protect the privacy of patients\' facial images in an era of rapid adoption of digital health technologies.

© 2022. The Author(s).

Nat Med: 15 Sep 2022; epub ahead of print
Yang Y, Lyu J, Wang R, Wen Q, ... Dai Q, Lin H
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109638
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Abstract

Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus.

Mackensen A, Müller F, Mougiakakos D, Böltz S, ... Krönke G, Schett G
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.

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

Nat Med: 15 Sep 2022; epub ahead of print
Mackensen A, Müller F, Mougiakakos D, Böltz S, ... Krönke G, Schett G
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109639
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Abstract

Anonymizing facial images to improve patient privacy.


To minimize the risks of inappropriately disclosing facial images of patients, we developed the digital mask to erase identifiable features while retaining disease-relevant features needed for diagnosis. The digital mask has shown the ability to evade recognition by human researchers and existing facial-recognition algorithms, and improves patients\' willingness to share medical information.

© 2022. Springer Nature America, Inc.

Nat Med: 15 Sep 2022; epub ahead of print
Nat Med: 15 Sep 2022; epub ahead of print | PMID: 36109640
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Abstract

Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial.

Chaft JE, Oezkan F, Kris MG, Bunn PA, ... Carbone DP, LCMC study investigators
In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

© 2022. The Author(s).

Nat Med: 12 Sep 2022; epub ahead of print
Chaft JE, Oezkan F, Kris MG, Bunn PA, ... Carbone DP, LCMC study investigators
Nat Med: 12 Sep 2022; epub ahead of print | PMID: 36097216
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Abstract

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF metastatic colorectal cancer.

Elez E, Ros J, Fernández J, Villacampa G, ... Tabernero J, Toledo RA
Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

© 2022. The Author(s).

Nat Med: 12 Sep 2022; epub ahead of print
Elez E, Ros J, Fernández J, Villacampa G, ... Tabernero J, Toledo RA
Nat Med: 12 Sep 2022; epub ahead of print | PMID: 36097219
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Abstract

Genetic risk factors have a substantial impact on healthy life years.

Jukarainen S, Kiiskinen T, Kuitunen S, Havulinna AS, ... Pirinen M, Ganna A
The impact of genetic variation on overall disease burden has not been comprehensively evaluated. We introduce an approach to estimate the effect of genetic risk factors on disability-adjusted life years (DALYs; \'lost healthy life years\'). We use genetic information from 735,748 individuals and consider 80 diseases. Rare variants had the highest effect on DALYs at the individual level. Among common variants, rs3798220 (LPA) had the strongest individual-level effect, with 1.18 DALYs from carrying 1 versus 0 copies. Being in the top 10% versus the bottom 90% of a polygenic score for multisite chronic pain had an effect of 3.63 DALYs. Some common variants had a population-level effect comparable to modifiable risk factors such as high sodium intake and low physical activity. Attributable DALYs vary between males and females for some genetic exposures. Genetic risk factors can explain a sizable number of healthy life years lost both at the individual and population level.

© 2022. The Author(s).

Nat Med: 12 Sep 2022; epub ahead of print
Jukarainen S, Kiiskinen T, Kuitunen S, Havulinna AS, ... Pirinen M, Ganna A
Nat Med: 12 Sep 2022; epub ahead of print | PMID: 36097220
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Abstract

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.

Haradhvala NJ, Leick MB, Maurer K, Gohil SH, ... Getz G, Maus MV
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

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

Nat Med: 12 Sep 2022; epub ahead of print
Haradhvala NJ, Leick MB, Maurer K, Gohil SH, ... Getz G, Maus MV
Nat Med: 12 Sep 2022; epub ahead of print | PMID: 36097221
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Abstract

Post-infusion CAR T cells identify patients resistant to CD19-CAR therapy.

Good Z, Spiegel JY, Sahaf B, Malipatlolla MB, ... Miklos DB, Mackall CL
Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.

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

Nat Med: 12 Sep 2022; epub ahead of print
Good Z, Spiegel JY, Sahaf B, Malipatlolla MB, ... Miklos DB, Mackall CL
Nat Med: 12 Sep 2022; epub ahead of print | PMID: 36097223
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Abstract

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial.

Baloh RH, Johnson JP, Avalos P, Allred P, ... Lewis RA, Svendsen CN
Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

© 2022. The Author(s).

Nat Med: 05 Sep 2022; epub ahead of print
Baloh RH, Johnson JP, Avalos P, Allred P, ... Lewis RA, Svendsen CN
Nat Med: 05 Sep 2022; epub ahead of print | PMID: 36064599
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Abstract

Long-term cardiac pathology in individuals with mild initial COVID-19 illness.

Puntmann VO, Martin S, Shchendrygina A, Hoffmann J, ... Schwenke C, Nagel E
Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77-177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274-383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

© 2022. The Author(s).

Nat Med: 05 Sep 2022; epub ahead of print
Puntmann VO, Martin S, Shchendrygina A, Hoffmann J, ... Schwenke C, Nagel E
Nat Med: 05 Sep 2022; epub ahead of print | PMID: 36064600
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Abstract

Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating.

Shivacharan RS, Rolle CE, Barbosa DAN, Cunningham TN, ... Lock JD, Halpern CH
Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach.

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

Nat Med: 29 Aug 2022; epub ahead of print
Shivacharan RS, Rolle CE, Barbosa DAN, Cunningham TN, ... Lock JD, Halpern CH
Nat Med: 29 Aug 2022; epub ahead of print | PMID: 36038628
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Abstract

Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma.

Scholler N, Perbost R, Locke FL, Jain MD, ... Bot A, Galon J
Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.

© 2022. The Author(s).

Nat Med: 29 Aug 2022; epub ahead of print
Scholler N, Perbost R, Locke FL, Jain MD, ... Bot A, Galon J
Nat Med: 29 Aug 2022; epub ahead of print | PMID: 36038629
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Abstract

Smartphone-based screening for atrial fibrillation: a pragmatic randomized clinical trial.

Rizas KD, Freyer L, Sappler N, von Stülpnagel L, ... Massberg S, Bauer A
Digital smart devices have the capability of detecting atrial fibrillation (AF), but the efficacy of this type of digital screening has not been directly compared to usual care for detection of treatment-relevant AF. In the eBRAVE-AF trial ( NCT04250220 ), we randomly assigned 5,551 policyholders of a German health insurance company who were free of AF at baseline (age 65 years (median; interquartile range (11) years, 31% females)) to digital screening (n = 2,860) or usual care (n = 2,691). In this siteless trial, for digital screening, participants used a certified app on their own smartphones to screen for irregularities in their pulse waves. Abnormal findings were evaluated by 14-day external electrocardiogram (ECG) loop recorders. The primary endpoint was newly diagnosed AF within 6 months treated with oral anti-coagulation by an independent physician not involved in the study. After 6 months, participants were invited to cross-over for a second study phase with reverse assignment for secondary analyses. The primary endpoint of the trial was met, as digital screening more than doubled the detection rate of treatment-relevant AF in both phases of the trial, with odds ratios of 2.12 (95% confidence interval (CI), 1.19-3.76; P = 0.010) and 2.75 (95% CI, 1.42-5.34; P = 0.003) in the first and second phases, respectively. This digital screening technology provides substantial benefits in detecting AF compared to usual care and has the potential for broad applicability due to its wide availability on ordinary smartphones. Future studies are needed to test whether digital screening for AF leads to better treatment outcomes.

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

Nat Med: 28 Aug 2022; epub ahead of print
Rizas KD, Freyer L, Sappler N, von Stülpnagel L, ... Massberg S, Bauer A
Nat Med: 28 Aug 2022; epub ahead of print | PMID: 36031651
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Abstract

Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER.

Jhund PS, Kondo T, Butt JH, Docherty KF, ... Solomon SD, McMurray JJV
Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82-0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65-0.78; P < 0.001) and MACEs (HR 0.90, 95% CI 0.81-1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).

© 2022. The Author(s).

Nat Med: 27 Aug 2022; epub ahead of print
Jhund PS, Kondo T, Butt JH, Docherty KF, ... Solomon SD, McMurray JJV
Nat Med: 27 Aug 2022; epub ahead of print | PMID: 36030328
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Abstract

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial.

Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, ... Gullo G, Rietschel P
First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.

© 2022. The Author(s).

Nat Med: 25 Aug 2022; epub ahead of print
Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, ... Gullo G, Rietschel P
Nat Med: 25 Aug 2022; epub ahead of print | PMID: 36008722
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Abstract

Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial.

Peters S, Dziadziuszko R, Morabito A, Felip E, ... Gandara DR, Mok T
Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.

© 2022. The Author(s).

Nat Med: 22 Aug 2022; epub ahead of print
Peters S, Dziadziuszko R, Morabito A, Felip E, ... Gandara DR, Mok T
Nat Med: 22 Aug 2022; epub ahead of print | PMID: 35995953
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Abstract

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

Gilbert PB, Huang Y, deCamp AC, Karuna S, ... Montefiori DC, Morris L
The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker-which quantifies the neutralization potency of antibodies in an individual\'s serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

© 2022. The Author(s).

Nat Med: 22 Aug 2022; epub ahead of print
Gilbert PB, Huang Y, deCamp AC, Karuna S, ... Montefiori DC, Morris L
Nat Med: 22 Aug 2022; epub ahead of print | PMID: 35995954
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Abstract

Artificial intelligence-enabled detection and assessment of Parkinson\'s disease using nocturnal breathing signals.

Yang Y, Yuan Y, Zhang G, Wang H, ... Dorsey R, Katabi D
There are currently no effective biomarkers for diagnosing Parkinson\'s disease (PD) or tracking its progression. Here, we developed an artificial intelligence (AI) model to detect PD and track its progression from nocturnal breathing signals. The model was evaluated on a large dataset comprising 7,671 individuals, using data from several hospitals in the United States, as well as multiple public datasets. The AI model can detect PD with an area-under-the-curve of 0.90 and 0.85 on held-out and external test sets, respectively. The AI model can also estimate PD severity and progression in accordance with the Movement Disorder Society Unified Parkinson\'s Disease Rating Scale (R = 0.94, P = 3.6 × 10-25). The AI model uses an attention layer that allows for interpreting its predictions with respect to sleep and electroencephalogram. Moreover, the model can assess PD in the home setting in a touchless manner, by extracting breathing from radio waves that bounce off a person\'s body during sleep. Our study demonstrates the feasibility of objective, noninvasive, at-home assessment of PD, and also provides initial evidence that this AI model may be useful for risk assessment before clinical diagnosis.

© 2022. The Author(s).

Nat Med: 22 Aug 2022; epub ahead of print
Yang Y, Yuan Y, Zhang G, Wang H, ... Dorsey R, Katabi D
Nat Med: 22 Aug 2022; epub ahead of print | PMID: 35995955
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Abstract

Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.

Hagey RJ, Elazar M, Pham EA, Tian S, ... Das R, Glenn JS
Influenza A virus\'s (IAV\'s) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV\'s genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term \'programmable antivirals\', with implications for antiviral prophylaxis and post-exposure therapy.

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

Nat Med: 18 Aug 2022; epub ahead of print
Hagey RJ, Elazar M, Pham EA, Tian S, ... Das R, Glenn JS
Nat Med: 18 Aug 2022; epub ahead of print | PMID: 35982307
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Impact:
Abstract

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer.

Chatila WK, Kim JK, Walch H, Marco MR, ... Sanchez-Vega F, Garcia-Aguilar J
The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

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

Nat Med: 15 Aug 2022; epub ahead of print
Chatila WK, Kim JK, Walch H, Marco MR, ... Sanchez-Vega F, Garcia-Aguilar J
Nat Med: 15 Aug 2022; epub ahead of print | PMID: 35970919
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Abstract

Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results.

Palmer CD, Rappaport AR, Davis MJ, Hart MG, ... Ferguson AR, Jooss K
Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 1012 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.

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

Nat Med: 15 Aug 2022; epub ahead of print
Palmer CD, Rappaport AR, Davis MJ, Hart MG, ... Ferguson AR, Jooss K
Nat Med: 15 Aug 2022; epub ahead of print | PMID: 35970920
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Abstract

Retrospective detection of asymptomatic monkeypox virus infections among male sexual health clinic attendees in Belgium.

De Baetselier I, Van Dijck C, Kenyon C, Coppens J, ... Van Esbroeck M, ITM Monkeypox study group
The magnitude of the 2022 multi-country monkeypox virus outbreak has surpassed any preceding outbreak. It is unclear whether asymptomatic or otherwise undiagnosed infections are fuelling this epidemic. We aimed to assess whether undiagnosed infections occurred among men attending a Belgian sexual health clinic in May 2022. We retrospectively screened 224 samples collected for gonorrhoea and chlamydia testing using a monkeypox virus (MPXV) PCR assay, and identified MPXV DNA-positive samples from four men. At the time of sampling, one man had a painful rash, and three men had reported no symptoms. Upon clinical examination 21 to 37 days later, these three men were free of clinical signs and they reported not having experienced any symptoms. Serology confirmed MPXV exposure in all three men, and MPXV was cultured from two cases. These findings show that certain cases of monkeypox remain undiagnosed, and suggest that testing and quarantining of individuals reporting symptoms may not suffice to contain the outbreak.

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

Nat Med: 12 Aug 2022; epub ahead of print
De Baetselier I, Van Dijck C, Kenyon C, Coppens J, ... Van Esbroeck M, ITM Monkeypox study group
Nat Med: 12 Aug 2022; epub ahead of print | PMID: 35961373
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Abstract

Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial.

Subbiah V, Cassier PA, Siena S, Garralda E, ... Fan Y, Curigliano G
Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion-positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35-77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib\'s potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors.

© 2022. The Author(s).

Nat Med: 12 Aug 2022; epub ahead of print
Subbiah V, Cassier PA, Siena S, Garralda E, ... Fan Y, Curigliano G
Nat Med: 12 Aug 2022; epub ahead of print | PMID: 35962206
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Abstract

Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer\'s disease.

Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, ... Suárez-Calvet M, Blennow K
Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer\'s disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer\'s disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer\'s disease clinical trials.

© 2022. The Author(s).

Nat Med: 11 Aug 2022; epub ahead of print
Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, ... Suárez-Calvet M, Blennow K
Nat Med: 11 Aug 2022; epub ahead of print | PMID: 35953717
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Abstract

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia.

Nadeu F, Royo R, Massoni-Badosa R, Playa-Albinyana H, ... Martín-Subero JI, Campo E
Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

© 2022. The Author(s).

Nat Med: 11 Aug 2022; epub ahead of print
Nadeu F, Royo R, Massoni-Badosa R, Playa-Albinyana H, ... Martín-Subero JI, Campo E
Nat Med: 11 Aug 2022; epub ahead of print | PMID: 35953718
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Abstract

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.

Nicholls SJ, Ditmarsch M, Kastelein JJ, Rigby SP, ... Alp NJ, Davidson MH
Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl-1) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly (P < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients.

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

Nat Med: 11 Aug 2022; epub ahead of print
Nicholls SJ, Ditmarsch M, Kastelein JJ, Rigby SP, ... Alp NJ, Davidson MH
Nat Med: 11 Aug 2022; epub ahead of print | PMID: 35953719
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Impact:
Abstract

Cellular senescence and senolytics: the path to the clinic.

Chaib S, Tchkonia T, Kirkland JL
Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies-including recent and ongoing clinical trials-for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.

© 2022. Springer Nature America, Inc.

Nat Med: 11 Aug 2022; epub ahead of print
Chaib S, Tchkonia T, Kirkland JL
Nat Med: 11 Aug 2022; epub ahead of print | PMID: 35953721
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Impact:
Abstract

Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial.

Bartsch R, Berghoff AS, Furtner J, Marhold M, ... Puhr R, Preusser M
Trastuzumab deruxtecan is an antibody-drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%. Fifteen patients were enrolled in the intention-to-treat population of patients who received at least one dose of study drug. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1-89.1%), thus meeting the predefined primary outcome. No new safety signals were observed and global quality-of-life and cognitive functioning were maintained over the treatment duration. In the TUXEDO-1 trial (NCT04752059, EudraCT 2020-000981-41), trastuzumab deruxtecan showed a high intracranial response rate in patients with active brain metastases from HER2-positive breast cancer and should be considered as a treatment option in this setting.

© 2022. The Author(s).

Nat Med: 08 Aug 2022; epub ahead of print
Bartsch R, Berghoff AS, Furtner J, Marhold M, ... Puhr R, Preusser M
Nat Med: 08 Aug 2022; epub ahead of print | PMID: 35941372
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Impact:
Abstract

Pepinemab antibody blockade of SEMA4D in early Huntington\'s disease: a randomized, placebo-controlled, phase 2 trial.

Feigin A, Evans EE, Fisher TL, Leonard JE, ... Zauderer M, Huntington Study Group SIGNAL investigators
SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington\'s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

© 2022. The Author(s).

Nat Med: 08 Aug 2022; epub ahead of print
Feigin A, Evans EE, Fisher TL, Leonard JE, ... Zauderer M, Huntington Study Group SIGNAL investigators
Nat Med: 08 Aug 2022; epub ahead of print | PMID: 35941373
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Abstract

Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein.

Jung H, Lee SY, Lim S, Choi HR, ... Chung WS, Kim CH
Clearing amyloid-β (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer\'s disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Here, we develop a phagocytosis inducer for Aβ consisting of a single-chain variable fragment of an Aβ-targeting monoclonal antibody fused with a truncated receptor binding domain of growth arrest-specific 6 (Gas6), a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors. This chimeric fusion protein (αAβ-Gas6) selectively eliminates Aβ plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, αAβ-Gas6 can induce synergistic clearance of Aβ by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with Aβ antibody treatment. Our results suggest that αAβ-Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.

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

Nat Med: 04 Aug 2022; epub ahead of print
Jung H, Lee SY, Lim S, Choi HR, ... Chung WS, Kim CH
Nat Med: 04 Aug 2022; epub ahead of print | PMID: 35927581
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Abstract

CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric β/β transfusion-dependent β-thalassemia.

Fu B, Liao J, Chen S, Li W, ... Liu M, Wu Y
Gene editing to disrupt the GATA1-binding site at the +58 BCL11A erythroid enhancer could induce γ-globin expression, which is a promising therapeutic strategy to alleviate β-hemoglobinopathy caused by HBB gene mutation. In the present study, we report the preliminary results of an ongoing phase 1/2 trial (NCT04211480) evaluating safety and efficacy of gene editing therapy in children with blood transfusion-dependent β-thalassemia (TDT). We transplanted BCL11A enhancer-edited, autologous, hematopoietic stem and progenitor cells into two children, one carrying the β00 genotype, classified as the most severe type of TDT. Primary endpoints included engraftment, overall survival and incidence of adverse events (AEs). Both patients were clinically well with multilineage engraftment, and all AEs to date were considered unrelated to gene editing and resolved after treatment. Secondary endpoints included achieving transfusion independence, editing rate in bone marrow cells and change in hemoglobin (Hb) concentration. Both patients achieved transfusion independence for >18 months after treatment, and their Hb increased from 8.2 and 10.8 g dl-1 at screening to 15.0 and 14.0 g dl-1 at the last visit, respectively, with 85.46% and 89.48% editing persistence in bone marrow cells. Exploratory analysis of single-cell transcriptome and indel patterns in edited peripheral blood mononuclear cells showed no notable side effects of the therapy.

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

Nat Med: 04 Aug 2022; epub ahead of print
Fu B, Liao J, Chen S, Li W, ... Liu M, Wu Y
Nat Med: 04 Aug 2022; epub ahead of print | PMID: 35922667
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Abstract

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

Tcheandjieu C, Zhu X, Hilliard AT, Clarke SL, ... O\'Donnell CJ, Assimes TL
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

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

Nat Med: 01 Aug 2022; epub ahead of print
Tcheandjieu C, Zhu X, Hilliard AT, Clarke SL, ... O'Donnell CJ, Assimes TL
Nat Med: 01 Aug 2022; epub ahead of print | PMID: 35915156
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Abstract

Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.

Sartore-Bianchi A, Pietrantonio F, Lonardi S, Mussolin B, ... Siena S, Bardelli A
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

© 2022. The Author(s).

Nat Med: 01 Aug 2022; epub ahead of print
Sartore-Bianchi A, Pietrantonio F, Lonardi S, Mussolin B, ... Siena S, Bardelli A
Nat Med: 01 Aug 2022; epub ahead of print | PMID: 35915157
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Abstract

Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.

Sapkota Y, Qiu W, Dixon SB, Wilson CL, ... Delaney A, Yasui Y
Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.

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

Nat Med: 25 Jul 2022; epub ahead of print
Sapkota Y, Qiu W, Dixon SB, Wilson CL, ... Delaney A, Yasui Y
Nat Med: 25 Jul 2022; epub ahead of print | PMID: 35879615
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Abstract

Symptoms and risk factors for long COVID in non-hospitalized adults.

Subramanian A, Nirantharakumar K, Hughes S, Myles P, ... Calvert M, Haroon S
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02-8.39), hair loss (3.99, 3.63-4.39), sneezing (2.77, 1.40-5.50), ejaculation difficulty (2.63, 1.61-4.28) and reduced libido (2.36, 1.61-3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.

© 2022. The Author(s).

Nat Med: 25 Jul 2022; epub ahead of print
Subramanian A, Nirantharakumar K, Hughes S, Myles P, ... Calvert M, Haroon S
Nat Med: 25 Jul 2022; epub ahead of print | PMID: 35879616
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Abstract

Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial.

Todo T, Ito H, Ino Y, Ohtsu H, ... Shibahara J, Tanaka M
This investigator-initiated, phase 2, single-arm trial primarily assessed the efficacy of G47∆, a triple-mutated, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial glioblastoma after radiation therapy and temozolomide (UMIN-CTR Clinical Trial Registry UMIN000015995). G47Δ was administered intratumorally and repeatedly for up to six doses. The primary endpoint of 1-yr survival rate after G47∆ initiation was 84.2% (95% confidence interval, 60.4-96.6; 16 of 19). The prespecified endpoint was met and the trial was terminated early. Regarding secondary endpoints, the median overall survival was 20.2 (16.8-23.6) months after G47∆ initiation and 28.8 (20.1-37.5) months from the initial surgery. The most common G47∆-related adverse event was fever (17 of 19) followed by vomiting, nausea, lymphocytopenia and leukopenia. On magnetic resonance imaging, enlargement of and contrast-enhancement clearing within the target lesion repeatedly occurred after each G47∆ administration, which was characteristic to this therapy. Thus, the best overall response in 2 yr was partial response in one patient and stable disease in 18 patients. Biopsies revealed increasing numbers of tumor-infiltrating CD4+/CD8+ lymphocytes and persistent low numbers of Foxp3+ cells. This study showed a survival benefit and good safety profile, which led to the approval of G47∆ as the first oncolytic virus product in Japan.

© 2022. The Author(s).

Nat Med: 21 Jul 2022; epub ahead of print
Todo T, Ito H, Ino Y, Ohtsu H, ... Shibahara J, Tanaka M
Nat Med: 21 Jul 2022; epub ahead of print | PMID: 35864254
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Abstract

Modeling global 80-80-80 blood pressure targets and cardiovascular outcomes.

Pickersgill SJ, Msemburi WT, Cobb L, Ide N, ... Xu X, Watkins DA
As the leading cause of death worldwide, cardiovascular diseases (CVDs) present major challenges for health systems. In this study, we analyzed the effects of better population blood pressure control in the context of a proposed 80-80-80 target: 80% of individuals with hypertension are screened and aware of their diagnosis; 80% of those who are aware are prescribed treatment; and 80% of those on treatment have achieved guideline-specified blood pressure targets. We developed a population CVD model using country-level evidence on CVD rates, blood pressure levels and hypertension intervention coverage. Under realistic implementation conditions, most countries could achieve 80-80-80 targets by 2040, reducing all-cause mortality by 4-7% (76-130 million deaths averted over 2022-2050) and slowing the rise in CVD expected from population growth and aging (110-200 million cases averted). Although populous middle-income countries would account for most of the reduced CVD cases and deaths, low-income countries would experience the largest reductions in disease rates.

© 2022. The Author(s).

Nat Med: 18 Jul 2022; epub ahead of print
Pickersgill SJ, Msemburi WT, Cobb L, Ide N, ... Xu X, Watkins DA
Nat Med: 18 Jul 2022; epub ahead of print | PMID: 35851877
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Abstract

The promise of precision medicine in rheumatology.

Guthridge JM, Wagner CA, James JA
Systemic autoimmune rheumatic diseases (SARDs) exhibit extensive heterogeneity in clinical presentation, disease course, and treatment response. Therefore, precision medicine - whereby treatment is tailored according to the underlying pathogenic mechanisms of an individual patient at a specific time - represents the \'holy grail\' in SARD clinical care. Current strategies include treat-to-target therapies and autoantibody testing for patient stratification; however, these are far from optimal. Recent innovations in high-throughput \'omic\' technologies are now enabling comprehensive profiling at multiple levels, helping to identify subgroups of patients who may taper off potentially toxic medications or better respond to current molecular targeted therapies. Such advances may help to optimize outcomes and identify new pathways for treatment, but there are many challenges along the path towards clinical translation. In this Review, we discuss recent efforts to dissect cellular and molecular heterogeneity across multiple SARDs and future directions for implementing stratification approaches for SARD treatment in the clinic.

© 2022. Springer Nature America, Inc.

Nat Med: 04 Jul 2022; epub ahead of print
Guthridge JM, Wagner CA, James JA
Nat Med: 04 Jul 2022; epub ahead of print | PMID: 35788174
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Abstract

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects.

Robertson NA, Latorre-Crespo E, Terradas-Terradas M, Lemos-Portela J, ... Kirschner K, Chandra T
Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

© 2022. The Author(s).

Nat Med: 04 Jul 2022; epub ahead of print
Robertson NA, Latorre-Crespo E, Terradas-Terradas M, Lemos-Portela J, ... Kirschner K, Chandra T
Nat Med: 04 Jul 2022; epub ahead of print | PMID: 35788175
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Abstract

Syndemics and clinical science.

Mendenhall E, Kohrt BA, Logie CH, Tsai AC
The theory of syndemics has received increasing attention in clinical medicine since the onset of the COVID-19 pandemic, due to the synergistic interactions of the disease with pre-existing political, structural, social and health conditions. In simple terms, syndemics are synergistically interacting epidemics that occur in a particular context with shared drivers. When policymakers ask why some communities have higher death rates from COVID-19 compared with other communities, those working from a syndemics framework argue that multiple factors synergistically work in tandem, and populations with the highest morbidity and mortality experience the greatest impact of these interactions. In this Perspective, we use specific case examples to illustrate these concepts. We discuss the emergence of syndemics, how epidemics interact, and what scientists, clinicians and policymakers can do with this information.

© 2022. Springer Nature America, Inc.

Nat Med: 01 Jul 2022; 28:1359-1362
Mendenhall E, Kohrt BA, Logie CH, Tsai AC
Nat Med: 01 Jul 2022; 28:1359-1362 | PMID: 35864249
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Abstract

Factors driving provider adoption of the TREWS machine learning-based early warning system and its effects on sepsis treatment timing.

Henry KE, Adams R, Parent C, Soleimani H, ... Wu AW, Saria S
Machine learning-based clinical decision support tools for sepsis create opportunities to identify at-risk patients and initiate treatments at early time points, which is critical for improving sepsis outcomes. In view of the increasing use of such systems, better understanding of how they are adopted and used by healthcare providers is needed. Here, we analyzed provider interactions with a sepsis early detection tool (Targeted Real-time Early Warning System), which was deployed at five hospitals over a 2-year period. Among 9,805 retrospectively identified sepsis cases, the early detection tool achieved high sensitivity (82% of sepsis cases were identified) and a high rate of adoption: 89% of all alerts by the system were evaluated by a physician or advanced practice provider and 38% of evaluated alerts were confirmed by a provider. Adjusting for patient presentation and severity, patients with sepsis whose alert was confirmed by a provider within 3 h had a 1.85-h (95% CI 1.66-2.00) reduction in median time to first antibiotic order compared to patients with sepsis whose alert was either dismissed, confirmed more than 3 h after the alert or never addressed in the system. Finally, we found that emergency department providers and providers who had previous interactions with an alert were more likely to interact with alerts, as well as to confirm alerts on retrospectively identified patients with sepsis. Beyond efforts to improve the performance of early warning systems, efforts to improve adoption are essential to their clinical impact and should focus on understanding providers\' knowledge of, experience with and attitudes toward such systems.

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

Nat Med: 01 Jul 2022; 28:1447-1454
Henry KE, Adams R, Parent C, Soleimani H, ... Wu AW, Saria S
Nat Med: 01 Jul 2022; 28:1447-1454 | PMID: 35864251
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Impact:
Abstract

Prospective, multi-site study of patient outcomes after implementation of the TREWS machine learning-based early warning system for sepsis.

Adams R, Henry KE, Sridharan A, Soleimani H, ... Wu AW, Saria S
Early recognition and treatment of sepsis are linked to improved patient outcomes. Machine learning-based early warning systems may reduce the time to recognition, but few systems have undergone clinical evaluation. In this prospective, multi-site cohort study, we examined the association between patient outcomes and provider interaction with a deployed sepsis alert system called the Targeted Real-time Early Warning System (TREWS). During the study, 590,736 patients were monitored by TREWS across five hospitals. We focused our analysis on 6,877 patients with sepsis who were identified by the alert before initiation of antibiotic therapy. Adjusting for patient presentation and severity, patients in this group whose alert was confirmed by a provider within 3 h of the alert had a reduced in-hospital mortality rate (3.3%, confidence interval (CI) 1.7, 5.1%, adjusted absolute reduction, and 18.7%, CI 9.4, 27.0%, adjusted relative reduction), organ failure and length of stay compared with patients whose alert was not confirmed by a provider within 3 h. Improvements in mortality rate (4.5%, CI 0.8, 8.3%, adjusted absolute reduction) and organ failure were larger among those patients who were additionally flagged as high risk. Our findings indicate that early warning systems have the potential to identify sepsis patients early and improve patient outcomes and that sepsis patients who would benefit the most from early treatment can be identified and prioritized at the time of the alert.

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

Nat Med: 01 Jul 2022; 28:1455-1460
Adams R, Henry KE, Sridharan A, Soleimani H, ... Wu AW, Saria S
Nat Med: 01 Jul 2022; 28:1455-1460 | PMID: 35864252
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Abstract

Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data.

Liu R, Rizzo S, Waliany S, Garmhausen MR, ... Copping R, Zou J
Quantifying the effectiveness of different cancer therapies in patients with specific tumor mutations is critical for improving patient outcomes and advancing precision medicine. Here we perform a large-scale computational analysis of 40,903 US patients with cancer who have detailed mutation profiles, treatment sequences and outcomes derived from electronic health records. We systematically identify 458 mutations that predict the survival of patients on specific immunotherapies, chemotherapy agents or targeted therapies across eight common cancer types. We further characterize mutation-mutation interactions that impact the outcomes of targeted therapies. This work demonstrates how computational analysis of large real-world data generates insights, hypotheses and resources to enable precision oncology.

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

Nat Med: 30 Jun 2022; epub ahead of print
Liu R, Rizzo S, Waliany S, Garmhausen MR, ... Copping R, Zou J
Nat Med: 30 Jun 2022; epub ahead of print | PMID: 35773542
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Impact:

This program is still in alpha version.