<div><h4>Genomic profiling informs diagnoses and treatment in vascular anomalies.</h4><i>Li D, Sheppard SE, March ME, Battig MR, ... Dori Y, Hakonarson H</i><br /><AbstractText>Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 01 Jun 2023; epub ahead of print</small></div>

<div><h4>Genetically adjusted PSA levels for prostate cancer screening.</h4><i>Kachuri L, Hoffmann TJ, Jiang Y, Berndt SI, ... Graff RE, Witte JS</i><br /><AbstractText>Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10<sup>-8</sup>) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS<sub>PSA</sub>) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10<sup>-14</sup>, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10<sup>-12</sup>, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10<sup>-4</sup>). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 01 Jun 2023; epub ahead of print</small></div>

<div><h4>Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation.</h4><i>Geoerger B, Schiff M, Penard-Lacronique V, Darin N, ... Ottolenghi C, De Botton S</i><br /><AbstractText>D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 29 May 2023; epub ahead of print</small></div>

<div><h4>Polygenic prediction of preeclampsia and gestational hypertension.</h4><i>Honigberg MC, Truong B, Khan RR, Xiao B, ... Laisk T, Natarajan P</i><br /><AbstractText>Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 29 May 2023; epub ahead of print</small></div>

<div><h4>Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer\'s disease.</h4><i>Bellaver B, Povala G, Ferreira PCL, Ferrari-Souza JP, ... Rosa-Neto P, Pascoal TA</i><br /><AbstractText>An unresolved question for the understanding of Alzheimer\'s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast<sup>+</sup>). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast<sup>+</sup> individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 29 May 2023; epub ahead of print</small></div>

<div><h4>Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance.</h4><i>Chu Y, Dai E, Li Y, Han G, ... Yee C, Wang L</i><br /><AbstractText>Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, T<sub>STR</sub>, characterized by heat shock gene expression. T<sub>STR</sub> cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8<sup>+</sup> cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of T<sub>STR</sub> cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 29 May 2023; epub ahead of print</small></div>

<div><h4>Propagative α-synuclein seeds as serum biomarkers for synucleinopathies.</h4><i>Okuzumi A, Hatano T, Matsumoto G, Nojiri S, ... Nukina N, Hattori N</i><br /><AbstractText>Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson\'s disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 29 May 2023; epub ahead of print</small></div>

<div><h4>Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial.</h4><i>Gao L, Lee BW, Chawla M, Kim J, ... Huang Y, Ji L</i><br /><AbstractText>Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist. In this phase 3, randomized, open-label trial, insulin-naive adults (≥18 years of age) with type 2 diabetes (T2D) uncontrolled on metformin (with or without a sulphonylurea) were randomized 1:1:1:1 to weekly tirzepatide 5 mg, 10 mg or 15 mg or daily insulin glargine at 66 hospitals in China, South Korea, Australia and India. The primary endpoint was non-inferiority of mean change in hemoglobin A1c (HbA1c) from baseline to week 40 after treatment with 10 mg and 15 mg of tirzepatide. Key secondary endpoints included non-inferiority and superiority of all tirzepatide doses in HbA1c reduction, proportions of patients achieving HbA1c < 7.0% and weight loss at week 40. A total of 917 patients (763 (83.2%) in China) were randomized to tirzepatide 5 mg (n = 230), 10 mg (n = 228) or 15 mg (n = 229) or insulin glargine (n = 230). All doses of tirzepatide were non-inferior and superior to insulin glargine for least squares mean (s.e.) reduction in HbA1c from baseline to week 40: tirzepatide 5 mg, 10 mg and 15 mg, -2.24% (0.07), -2.44% (0.07) and -2.49% (0.07), respectively, and insulin glargine, -0.95% (0.07), with a treatment difference ranging from -1.29% to -1.54% (all P < 0.001). Proportions of patients achieving HbA1c < 7.0% at week 40 were greater in tirzepatide 5-mg (75.4%), 10-mg (86.0%) and 15-mg (84.4%) groups compared to insulin glargine (23.7%) (all P < 0.001). All tirzepatide doses led to superior body weight reduction at week 40: tirzepatide 5 mg, 10 mg and 15 mg, -5.0 kg (-6.5%), -7.0 kg (-9.3%) and -7.2 kg (-9.4%), respectively, compared to insulin glargine, 1.5 kg (+2.1%) (all P < 0.001). The most common adverse events with tirzepatide were mild to moderate decreased appetite, diarrhea and nausea. No severe hypoglycemia was reported. Tirzepatide demonstrated superior reductions in HbA1c versus insulin glargine in an Asia-Pacific, predominately Chinese, population with T2D and was generally well tolerated. ClinicalTrials.gov registration: NCT04093752 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 25 May 2023; epub ahead of print</small></div>

<div><h4>Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial.</h4><i>Hosgood SA, Callaghan CJ, Wilson CH, Smith L, ... Bates L, Nicholson ML</i><br /><AbstractText>Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 25 May 2023; epub ahead of print</small></div>

<div><h4>Fair pathways to net-zero healthcare.</h4><i>Bhopal A, Norheim OF</i><br /><AbstractText>Over the past decade, it has become clear that the health sector is not only at risk from climate change but also a major polluter of greenhouse gases. In November 2021, the World Health Organization and partners launched the COP26 Health Programme for sustainable, climate-resilient and low-carbon health systems, and have since established the Alliance for Transformative Action on Climate and Health to support its implementation. Given the wide variation in health financing, carbon emissions and unmet health needs across the world, fair sharing of the remaining carbon budget and health gains will be critical. In this Perspective, we explore the challenges and opportunities of healthcare decarbonization, outlining the principles of fair pathways to net-zero healthcare that are attentive to health and socioeconomic inequalities within and between countries.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 18 May 2023; epub ahead of print</small></div>

<div><h4>An integrated tumor, immune and microbiome atlas of colon cancer.</h4><i>Roelands J, Kuppen PJK, Ahmed EI, Mall R, ... Hendrickx W, Bedognetti D</i><br /><AbstractText>The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 18 May 2023; epub ahead of print</small></div>

<div><h4>Resilience to autosomal dominant Alzheimer\'s disease in a Reelin-COLBOS heterozygous man.</h4><i>Lopera F, Marino C, Chandrahas AS, O\'Hare M, ... Arboleda-Velasquez JF, Quiroz YT</i><br /><AbstractText>We characterized the world\'s second case with ascertained extreme resilience to autosomal dominant Alzheimer\'s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 15 May 2023; epub ahead of print</small></div>

<div><h4>Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results.</h4><i>Heczey A, Xu X, Courtney AN, Tian G, ... Dotti G, Metelitsa LS</i><br /><AbstractText>Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L<sup>+</sup>NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 15 May 2023; epub ahead of print</small></div>

<div><h4>Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.</h4><i>Nassiri F, Patil V, Yefet LS, Singh O, ... Lang FF, Zadeh G</i><br /><AbstractText>Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 15 May 2023; epub ahead of print</small></div>

<div><h4>Accelerated waning of the humoral response to COVID-19 vaccines in obesity.</h4><i>van der Klaauw AA, Horner EC, Pereyra-Gerber P, Agrawal U, ... Farooqi IS, Thaventhiran JED</i><br /><AbstractText>Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m<sup>2</sup>) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m<sup>2</sup>). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 11 May 2023; epub ahead of print</small></div>

<div><h4>Machine learning for diagnosis of myocardial infarction using cardiac troponin concentrations.</h4><i>Doudesis D, Lee KK, Boeddinghaus J, Bularga A, ... Mills NL, CoDE-ACS Investigators</i><br /><AbstractText>Although guidelines recommend fixed cardiac troponin thresholds for the diagnosis of myocardial infarction, troponin concentrations are influenced by age, sex, comorbidities and time from symptom onset. To improve diagnosis, we developed machine learning models that integrate cardiac troponin concentrations at presentation or on serial testing with clinical features and compute the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) score (0-100) that corresponds to an individual\'s probability of myocardial infarction. The models were trained on data from 10,038 patients (48% women), and their performance was externally validated using data from 10,286 patients (35% women) from seven cohorts. CoDE-ACS had excellent discrimination for myocardial infarction (area under curve, 0.953; 95% confidence interval, 0.947-0.958), performed well across subgroups and identified more patients at presentation as low probability of having myocardial infarction than fixed cardiac troponin thresholds (61 versus 27%) with a similar negative predictive value and fewer as high probability of having myocardial infarction (10 versus 16%) with a greater positive predictive value. Patients identified as having a low probability of myocardial infarction had a lower rate of cardiac death than those with intermediate or high probability 30 days (0.1 versus 0.5 and 1.8%) and 1 year (0.3 versus 2.8 and 4.2%; P < 0.001 for both) from patient presentation. CoDE-ACS used as a clinical decision support system has the potential to reduce hospital admissions and have major benefits for patients and health care providers.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 11 May 2023; epub ahead of print</small></div>

<div><h4>Communicating health information with visual displays.</h4><i>Woloshin S, Yang Y, Fischhoff B</i><br /><AbstractText>Well-designed visual displays have the power to convey health messages in clear, effective ways to non-experts, including journalists, patients and policymakers. Poorly designed visual displays, however, can confuse and alienate recipients, undermining health messages. In this Perspective, we propose a structured framework for effective visual communication of health information, using case examples of three common communication tasks: comparing treatment options, interpreting test results, and evaluating risk scenarios. We also show simple, practical ways to evaluate a design\'s success and guide improvements. The proposed framework is grounded in research on health risk communication, visualization and decision science, as well as our experience in communicating health data.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 08 May 2023; epub ahead of print</small></div>

<div><h4>A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories.</h4><i>Placido D, Yuan B, Hjaltelin JX, Zheng C, ... Brunak S, Sander C</i><br /><AbstractText>Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36 months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve = 0.88 and decreases to AUROC (3m) = 0.83 when disease events within 3 months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50 years. Cross-application of the Danish model to US-VA data had lower performance (AUROC = 0.71), and retraining was needed to improve performance (AUROC = 0.78, AUROC (3m) = 0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 08 May 2023; epub ahead of print</small></div>

<div><h4>An automated histological classification system for precision diagnostics of kidney allografts.</h4><i>Yoo D, Goutaudier V, Divard G, Gueguen J, ... Rabant M, Loupy A</i><br /><AbstractText>For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 04 May 2023; epub ahead of print</small></div>

<div><h4>Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.</h4><i>Yosipovitch G, Mollanazar N, Ständer S, Kwatra SG, ... Bansal A, O\'Malley JT</i><br /><AbstractText>Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8-57.7 for the difference, P < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3-31.2; P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 04 May 2023; epub ahead of print</small></div>

<div><h4>The transcriptional and regulatory identity of erythropoietin producing cells.</h4><i>Kragesteen BK, Giladi A, David E, Halevi S, ... Wenger RH, Amit I</i><br /><AbstractText>Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>Multi-organ landscape of therapy-resistant melanoma.</h4><i>Liu S, Dharanipragada P, Lomeli SH, Wang Y, ... Moschos SJ, Lo RS</i><br /><AbstractText>Metastasis and failure of present-day therapies represent the most common causes of mortality in patients with cutaneous melanoma. To identify the underlying genetic and transcriptomic landscapes, in this study we analyzed multi-organ metastases and tumor-adjacent tissues from 11 rapid autopsies after treatment with MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) and death due to acquired resistance. Either treatment elicits shared genetic alterations that suggest immune-evasive, cross-therapy resistance mechanisms. Large, non-clustered deletions, inversions and inter-chromosomal translocations dominate rearrangements. Analyzing data from separate melanoma cohorts including 345 therapy-naive patients and 35 patients with patient-matched pre-treatment and post-acquired resistance tumor samples, we performed cross-cohort analyses to identify MAPKi and ICB as respective contributors to gene amplifications and deletions enriched in autopsy versus therapy-naive tumors. In the autopsy cohort, private/late mutations and structural variants display shifted mutational and rearrangement signatures, with MAPKi specifically selecting for signatures of defective homologous-recombination, mismatch and base-excision repair. Transcriptomic signatures and crosstalks with tumor-adjacent macroenvironments nominated organ-specific adaptive pathways. An immune-desert, CD8<sup>+</sup>-macrophage-biased archetype, T-cell exhaustion and type-2 immunity characterized the immune contexture. This multi-organ analysis of therapy-resistant melanoma presents preliminary insights with potential to improve therapeutic strategies.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>CanScreen5, a global repository for breast, cervical and colorectal cancer screening programs.</h4><i>Zhang L, Mosquera I, Lucas E, Rol ML, ... Basu P, CanScreen5 collaborators</i><br /><AbstractText>The CanScreen5 project is a global cancer screening data repository that aims to report the status and performance of breast, cervical and colorectal cancer screening programs using a harmonized set of criteria and indicators. Data collected mainly from the Ministry of Health in each country underwent quality validation and ultimately became publicly available through a Web-based portal. Until September 2022, 84 participating countries reported data for breast (n = 57), cervical (n = 75) or colorectal (n = 51) cancer screening programs in the repository. Substantial heterogeneity was observed regarding program organization and performance. Reported screening coverage ranged from 1.7% (Bangladesh) to 85.5% (England, United Kingdom) for breast cancer, from 2.1% (Côte d\'Ivoire) to 86.3% (Sweden) for cervical cancer, and from 0.6% (Hungary) to 64.5% (the Netherlands) for colorectal cancer screening programs. Large variability was observed regarding compliance to further assessment of screening programs and detection rates reported for precancers and cancers. A concern is lack of data to estimate performance indicators across the screening continuum. This underscores the need for programs to incorporate quality assurance protocols supported by robust information systems. Program organization requires improvement in resource-limited settings, where screening is likely to be resource-stratified and tailored to country-specific situations.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>A shared neural basis underlying psychiatric comorbidity.</h4><i>Xie C, Xiang S, Shen C, Peng X, ... STRATIFY Consortium, ZIB Consortium</i><br /><AbstractText>Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the Stratify Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants.</h4><i>Wilkins D, Yuan Y, Chang Y, Aksyuk AA, ... Villafana T, Esser MT</i><br /><AbstractText>Nirsevimab is an extended half-life monoclonal antibody specific for the prefusion conformation of the respiratory syncytial virus (RSV) F protein, which has been studied in preterm and full-term infants in the phase 2b and phase 3 MELODY trials. We analyzed serum samples collected from 2,143 infants during these studies to characterize baseline levels of RSV-specific immunoglobulin G antibodies and neutralizing antibodies (NAbs), duration of RSV NAb levels following nirsevimab administration, the risk of RSV exposure during the first year of life and the infant\'s adaptive immune response to RSV following nirsevimab administration. Baseline RSV antibody levels varied widely; consistent with reports that maternal antibodies are transferred late in the third trimester, preterm infants had lower baseline RSV antibody levels than full-term infants. Nirsevimab recipients had RSV NAb levels >140-fold higher than baseline at day 31 and remained >50-fold higher at day 151 and >7-fold higher at day 361. Similar seroresponse rates to the postfusion form of RSV F protein in nirsevimab recipients (68-69%) compared with placebo recipients (63-70%; not statistically significant) suggest that while nirsevimab protects from RSV disease, it still allows an active immune response. In summary, nirsevimab provided sustained, high levels of NAb throughout an infant\'s first RSV season and prevented RSV disease while allowing the development of an immune response to RSV.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Tau-targeting antisense oligonucleotide MAPT in mild Alzheimer\'s disease: a phase 1b, randomized, placebo-controlled trial.</h4><i>Mummery CJ, Börjesson-Hanson A, Blackburn DJ, Vijverberg EGB, ... Junge C, Lane RM</i><br /><AbstractText>Tau plays a key role in Alzheimer\'s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPT<sub>Rx</sub>) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPT<sub>Rx</sub>. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPT<sub>Rx</sub> or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPT<sub>Rx</sub> pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPT<sub>Rx</sub> and 12 to placebo. Adverse events were reported in 94% of MAPT<sub>Rx</sub>-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPT<sub>Rx</sub>-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPT<sub>Rx</sub> groups. Clinicaltrials.gov registration number: NCT03186989 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Simulation-based estimates and projections of global, regional and country-level maternal mortality by cause, 1990-2050.</h4><i>Ward ZJ, Atun R, King G, Sequeira Dmello B, Goldie SJ</i><br /><AbstractText>Maternal mortality is a major global health challenge. Although progress has been made globally in reducing maternal deaths, measurement remains challenging given the many causes and frequent underreporting of maternal deaths. We developed the Global Maternal Health microsimulation model for women in 200 countries and territories, accounting for individual fertility preferences and clinical histories. Demographic, epidemiologic, clinical and health system data were synthesized from multiple sources, including the medical literature, Civil Registration Vital Statistics systems and Demographic and Health Survey data. We calibrated the model to empirical data from 1990 to 2015 and assessed the predictive accuracy of our model using indicators from 2016 to 2020. We projected maternal health indicators from 1990 to 2050 for each country and estimate that between 1990 and 2020 annual global maternal deaths declined by over 40% from 587,500 (95% uncertainty intervals (UI) 520,600-714,000) to 337,600 (95% UI 307,900-364,100), and are projected to decrease to 327,400 (95% UI 287,800-360,700) in 2030 and 320,200 (95% UI 267,100-374,600) in 2050. The global maternal mortality ratio is projected to decline to 167 (95% UI 142-188) in 2030, with 58 countries above 140, suggesting that on current trends, maternal mortality Sustainable Development Goal targets are unlikely to be met. Building on the development of our structural model, future research can identify context-specific policy interventions that could allow countries to accelerate reductions in maternal deaths.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 20 Apr 2023; epub ahead of print</small></div>

<div><h4>A simulation-based comparative effectiveness analysis of policies to improve global maternal health outcomes.</h4><i>Ward ZJ, Atun R, King G, Sequeira Dmello B, Goldie SJ</i><br /><AbstractText>The Sustainable Development Goals include a target to reduce the global maternal mortality ratio (MMR) to less than 70 maternal deaths per 100,000 live births by 2030, with no individual country exceeding 140. However, on current trends the goals are unlikely to be met. We used the empirically calibrated Global Maternal Health microsimulation model, which simulates individual women in 200 countries and territories to evaluate the impact of different interventions and strategies from 2022 to 2030. Although individual interventions yielded fairly small reductions in maternal mortality, integrated strategies were more effective. A strategy to simultaneously increase facility births, improve the availability of clinical services and quality of care at facilities, and improve linkages to care would yield a projected global MMR of 72 (95% uncertainty interval (UI) = 58-87) in 2030. A comprehensive strategy adding family planning and community-based interventions would have an even larger impact, with a projected MMR of 58 (95% UI = 46-70). Although integrated strategies consisting of multiple interventions will probably be needed to achieve substantial reductions in maternal mortality, the relative priority of different interventions varies by setting. Our regional and country-level estimates can help guide priority setting in specific contexts to accelerate improvements in maternal health.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 20 Apr 2023; epub ahead of print</small></div>

<div><h4>Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.</h4><i>Crees ZD, Rettig MP, Jayasinghe RG, Stockerl-Goldstein K, ... Vij R, DiPersio JF</i><br /><AbstractText>Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34<sup>+</sup> hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10<sup>6</sup> CD34<sup>+</sup> cells kg<sup>-1</sup> within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34<sup>+</sup> HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.</h4><i>Duperron MG, Knol MJ, Le Grand Q, Evans TE, ... Adams HHH, Debette S</i><br /><AbstractText>Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Consensus recommendations on how to assess the quality of surgical interventions.</h4><i>Domenghino A, Walbert C, Birrer DL, Puhan MA, Clavien PA, Outcome4Medicine consensus group</i><br /><AbstractText>Postoperative complications represent a major public health burden worldwide. Without standardized, clinically relevant and universally applied endpoints, the evaluation of surgical interventions remains ill-defined and inconsistent, opening the door for biased interpretations and hampering patient-centered health care delivery. We conducted a Jury-based consensus conference incorporating the perspectives of different stakeholders, who based their recommendations on the work of nine panels of experts. The recommendations cover the selection of postoperative outcomes from the perspective of patients and other stakeholders, comparison and interpretation of outcomes, consideration of cultural and demographic factors, and strategies to deal with unwarranted outcomes. With the recommendations developed exclusively by the Jury, we provide a framework for surgical outcome assessment and quality improvement after medical interventions, that integrates the main stakeholders\' perspectives.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Incident type 2 diabetes attributable to suboptimal diet in 184 countries.</h4><i>O\'Hearn M, Lara-Castor L, Cudhea F, Miller V, ... Mozaffarian D, Global Dietary Database</i><br /><AbstractText>The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8-14.4 million) incident T2D cases, representing 70.3% (68.8-71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0-27.1%)), excess refined rice and wheat intake (24.6% (22.3-27.2%)) and excess processed meat intake (20.3% (18.3-23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4-87.7%)) and Latin America and the Caribbean (81.8% (80.1-83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1-60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.</h4><i>Subbiah V, Kreitman RJ, Wainberg ZA, Gazzah A, ... Ilankumaran P, Bang YJ</i><br /><AbstractText>BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 14 Apr 2023; epub ahead of print</small></div>

<div><h4>Salt substitution and salt-supply restriction for lowering blood pressure in elderly care facilities: a cluster-randomized trial.</h4><i>Yuan Y, Jin A, Neal B, Feng X, ... Labarthe D, Wu Y</i><br /><AbstractText>There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (-7.1 mmHg, 95% confidence interval (CI) -10.5 to -3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure. Salt substitute also lowered diastolic blood pressure (-1.9 mmHg, 95% CI -3.6 to -0.2) and resulted in fewer cardiovascular events (hazard ratio (HR) 0.60, 95% CI 0.38-0.96), but had no effect on total mortality (HR 0.84, 95% CI 0.63-1.13). From a safety standpoint, salt substitute increased mean serum potassium and led to more frequent biochemical hyperkalemia, but was not associated with adverse clinical outcomes. In contrast, salt restriction had no effect on any study outcome. The results of this trial indicate that use of salt substitute, but not efforts to restrict salt supply, may achieve blood pressure lowering and deliver health benefits to residents of elderly care facilities in China. Clinicaltrials.gov registration: NCT03290716.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 13 Apr 2023; epub ahead of print</small></div>

<div><h4>Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.</h4><i>Karasaki T, Moore DA, Veeriah S, Naceur-Lombardelli C, ... Swanton C, Jamal-Hanjani M</i><br /><AbstractText>Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and \'tumor spread through air spaces\' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.</AbstractText><br /><br />© 2023. The Author(s) under exclusive license to Springer Nature America, Inc.<br /><br /><small>Nat Med: 12 Apr 2023; epub ahead of print</small></div>

<div><h4>Body composition and lung cancer-associated cachexia in TRACERx.</h4><i>Al-Sawaf O, Weiss J, Skrzypski M, Lam JM, ... Jamal-Hanjani M, Swanton C</i><br /><AbstractText>Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.</AbstractText><br /><br />© 2023. The Author(s) under exclusive license to Springer Nature America, Inc.<br /><br /><small>Nat Med: 12 Apr 2023; epub ahead of print</small></div>

<div><h4>Community-integrated self-collected HPV-based cervix screening in a low-resource rural setting: a pragmatic, cluster-randomized trial.</h4><i>Gottschlich A, Payne BA, Trawin J, Albert A, ... Nakisige C, Ogilvie G</i><br /><AbstractText>Effective approaches to improve coverage of self-collected human papillomavirus (HPV)-based cervix screening (SCS) as well as attendance at treatment for HPV-positive participants are needed to inform policy on optimal integration of cervical cancer screening programs within existing infrastructure in low-resource settings. ASPIRE Mayuge was a pragmatic cluster-randomized trial in rural Mayuge district, Uganda, comparing the superiority of two recruitment implementation strategies for SCS: Door-to-Door versus Community Health Day. Villages were randomized (unblinded) to a strategy, and participants aged 25-49 years with no previous history of hysterectomy or treatment for cervical cancer or pre-cancer were eligible. Participants completed a survey and participated in SCS. The primary outcome was rate of attendance at treatment after a positive SCS. The trial randomized 31 villages and 2,019 participants included in these analyses (Door-to-Door: 16 clusters, 1,055 participants; Community Health Day: 15 clusters, 964 participants). Among HPV-positive participants, attendance at treatment rates were 75% (Door-to-Door) and 67% (Community Health Day) (P = 0.049). Participants in the Community Health Day intervention were less likely to attend treatment compared to Door-to-Door (risk ratio = 0.78, 95% confidence interval: 0.64-0.96). No adverse events were reported. Policymakers in low-resource settings can use these results to guide implementation of SCS programs. ISRCTN registration: 12767014 . ClinicalTrials.gov registration: NCT04000503 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 10 Apr 2023; epub ahead of print</small></div>

<div><h4>Tumor inflammation-associated neurotoxicity.</h4><i>Mahdi J, Dietrich J, Straathof K, Roddie C, ... Mackall CL, Monje M</i><br /><AbstractText>Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of \'pseudoprogression,\' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 06 Apr 2023; epub ahead of print</small></div>

<div><h4>Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial.</h4><i>Teong XT, Liu K, Vincent AD, Bensalem J, ... Hutchison AT, Heilbronn LK</i><br /><AbstractText>Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the \'fasting\' day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m<sup>-</sup><sup>2</sup>) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (-10.10 (95% confidence interval -14.08, -6.11) versus -3.57 (95% confidence interval -7.72, 0.57) mg dl<sup>-1</sup> min<sup>-1</sup>; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 06 Apr 2023; epub ahead of print</small></div>

<div><h4>Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality.</h4><i>Tian YE, Cropley V, Maier AB, Lautenschlager NT, Breakspear M, Zalesky A</i><br /><AbstractText>Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ\'s biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 06 Apr 2023; epub ahead of print</small></div>

<div><h4>Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial.</h4><i>Shenderov E, De Marzo AM, Lotan TL, Wang H, ... Pardoll DM, Antonarakis ES</i><br /><AbstractText>B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA<sub>0</sub>) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA<sub>0</sub> with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA<sub>0</sub> rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 03 Apr 2023; epub ahead of print</small></div>

<div><h4>Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial.</h4><i>Saba NF, Steuer CE, Ekpenyong A, McCook-Veal A, ... Teng Y, Chung CH</i><br /><AbstractText>Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8<sup>+</sup> T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7-32.9) and 68.4% (95% CI = 45.1%-83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2-19.6) and 54% (95% CI = 31.5%-72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8<sup>+</sup> T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218 .</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 03 Apr 2023; epub ahead of print</small></div>

<div><h4>Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.</h4><i>Goldsmith KC, Park JR, Kayser K, Malvar J, ... Marachelian A, Mossé YP</i><br /><AbstractText>Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and <sup>123</sup>I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m<sup>2</sup>/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m<sup>2</sup>. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib\'s rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 03 Apr 2023; epub ahead of print</small></div>

<div><h4>Interactions between the lipidome and genetic and environmental factors in autism.</h4><i>Yap CX, Henders AK, Alvares GA, Giles C, ... Wray NR, Gratten J</i><br /><AbstractText>Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for example, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis (n = 8), sleep disturbances (n = 20) and cognitive function (n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster. We explored the interplay of environmental factors with neurodevelopment and the lipidome, finding that sleep disturbances and unhealthy diet have a convergent lipidome profile (with potential mediation by the microbiome) that is also independently associated with poorer adaptive function. In contrast, ASD lipidome differences were accounted for by dietary differences and sleep disturbances. We identified a large chr19p13.2 copy number variant genetic deletion spanning the LDLR gene and two high-confidence ASD genes (ELAVL3 and SMARCA4) in one child with an ASD diagnosis and widespread low-density lipoprotein-related lipidome derangements. Lipidomics captures the complexity of neurodevelopment, as well as the biological effects of conditions that commonly affect quality of life among autistic people.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 01 Apr 2023; 29:936-949</small></div>

<div><h4>Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.</h4><i>Glitza Oliva IC, Ferguson SD, Bassett R, Foster AP, ... Tawbi HA, Davies MA</i><br /><AbstractText>There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 30 Mar 2023; epub ahead of print</small></div>

<div><h4>Determinants of COVID-19 vaccine fatigue.</h4><i>Stamm TA, Partheymüller J, Mosor E, Ritschl V, ... Alunno A, Eberl JM</i><br /><AbstractText>There is growing concern that Coronavirus Disease 2019 (COVID-19) vaccine fatigue will be a major obstacle in maintaining immunity in the general population. In this study, we assessed vaccine acceptance in future scenarios in two conjoint experiments, investigating determinants such as new vaccines, communication, costs/incentives and legal rules. The experiments were embedded in an online survey (n = 6,357 participants) conducted in two European countries (Austria and Italy). Our results suggest that vaccination campaigns should be tailored to subgroups based on their vaccination status. Among the unvaccinated, campaign messages conveying community spirit had a positive effect (0.343, confidence interval (CI) 0.019-0.666), whereas offering positive incentives, such as a cash reward (0.722, CI 0.429-1.014) or voucher (0.670, CI 0.373-0.967), was pivotal to the decision-making of those vaccinated once or twice. Among the triple vaccinated, vaccination readiness increased when adapted vaccines were offered (0.279, CI 0.182-0.377), but costs (-0.795, CI -0.935 to -0.654) and medical dissensus (-0.161, CI -0.293 to -0.030) reduced their likelihood to get vaccinated. We conclude that failing to mobilize the triple vaccinated is likely to result in booster vaccination rates falling short of expectations. For long-term success, measures fostering institutional trust should be considered. These results provide guidance to those responsible for future COVID-19 vaccination campaigns.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>Maternal third dose of BNT162b2 mRNA vaccine and risk of infant COVID-19 hospitalization.</h4><i>Lipschuetz M, Guedalia J, Cohen SM, Sompolinsky Y, ... Calderon-Margalit R, Beharier O</i><br /><AbstractText>Infants are at a higher risk of Coronavirus Disease 2019 (COVID-19)-related hospitalizations compared to older children. In this study, we investigated the effect of the recommended third maternal dose of BNT162b2 COVID-19 vaccine during pregnancy on rates of infant COVID-19-related hospitalizations. We conducted a nationwide cohort study of all live-born infants delivered in Israel between 24 August 2021 and 15 March 2022 to estimate the effectiveness of the third booster dose versus the second dose against infant COVID-19-related hospitalizations. Data were analyzed for the overall study period, and the Delta and Omicron periods were analyzed separately. Cox proportional hazard regression models estimated hazard ratios and 95% confidence intervals (CIs) for infant hospitalizations according to maternal vaccination status at delivery. Among 48,868 live-born infants included in the analysis, rates of COVID-19 hospitalization were 0.4%, 0.6% and 0.7% in the third-dose, second-dose and unvaccinated groups, respectively. Compared to the second dose, the third dose was associated with reduced infant hospitalization with estimated effectiveness of 53% (95% CI: 36-65%). Greater protection was associated with a shorter interval between vaccination and delivery. A third maternal dose during pregnancy reduced the risk of infant hospitalization for COVID-19 during the first 4 months of life, supporting clinical and public health guidance for maternal booster vaccination to prevent infant COVID-19 hospitalization.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 23 Mar 2023; epub ahead of print</small></div>

<div><h4>Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging.</h4><i>Hollon T, Jiang C, Chowdury A, Nasir-Moin M, ... Lee H, Orringer DA</i><br /><AbstractText>Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid (<90 seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma (n = 153) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of 93.3 ± 1.6%. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 23 Mar 2023; epub ahead of print</small></div>

<div><h4>Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention.</h4><i>Watanabe K, Wilmanski T, Diener C, Earls JC, ... Price ND, Rappaport N</i><br /><AbstractText>Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations and is a risk factor for multiple chronic diseases. Here we report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, whereas proteomics-inferred BMI exhibited greater resistance to change. Our analyses further identified blood analyte-analyte associations that were modified by metabolomics-inferred BMI and partially reversed in individuals with metabolic obesity during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a resource to quantify metabolic health for predictive and preventive medicine.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 20 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardiometabolic health, diet and the gut microbiome: a meta-omics perspective.</h4><i>Valles-Colomer M, Menni C, Berry SE, Valdes AM, Spector TD, Segata N</i><br /><AbstractText>Cardiometabolic diseases have become a leading cause of morbidity and mortality globally. They have been tightly linked to microbiome taxonomic and functional composition, with diet possibly mediating some of the associations described. Both the microbiome and diet are modifiable, which opens the way for novel therapeutic strategies. High-throughput omics techniques applied on microbiome samples (meta-omics) hold the unprecedented potential to shed light on the intricate links between diet, the microbiome, the metabolome and cardiometabolic health, with a top-down approach. However, effective integration of complementary meta-omic techniques is an open challenge and their application on large cohorts is still limited. Here we review meta-omics techniques and discuss their potential in this context, highlighting recent large-scale efforts and the novel insights they provided. Finally, we look to the next decade of meta-omics research and discuss various translational and clinical pathways to improving cardiometabolic health.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 17 Mar 2023; epub ahead of print</small></div>

<div><h4>Diagnostic classification of childhood cancer using multiscale transcriptomics.</h4><i>Comitani F, Nash JO, Cohen-Gogo S, Chang AI, ... Irwin MS, Shlien A</i><br /><AbstractText>The causes of pediatric cancers\' distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 17 Mar 2023; epub ahead of print</small></div>

<div><h4>Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.</h4><i>Sturm D, Capper D, Andreiuolo F, Gessi M, ... Pfister SM, Jones DTW</i><br /><AbstractText>The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer.</h4><i>Assaf ZJF, Zou W, Fine AD, Socinski MA, ... Shames DS, Schulze K</i><br /><AbstractText>One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0-5.3), P < 0.001; median 7.1 versus 22.3 months for high- versus low-intermediate risk) and with partial response (HR = 3.3 (1.7-6.4), P < 0.001; median 8.8 versus 28.6 months). The model also identified high-risk patients in an external validation cohort from the randomized phase 3 OAK study of ICI versus chemo in NSCLC (OS HR = 3.73 (1.83-7.60), P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.</h4><i>Larrayoz M, Garcia-Barchino MJ, Celay J, Etxebeste A, ... Prosper F, Martinez-Climent JA</i><br /><AbstractText>The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8<sup>+</sup> T cells with reduced immunosuppressive regulatory T (T<sub>reg</sub>) cells, while late MYC acquisition in slow progressors was associated with lower CD8<sup>+</sup> T cell infiltration and more abundant T<sub>reg</sub> cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8<sup>+</sup> T cells versus T<sub>reg</sub> cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8<sup>+</sup> T/T<sub>reg</sub> cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8<sup>+</sup> T cell cytotoxicity or depleting T<sub>reg</sub> cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial.</h4><i>Cascone T, Leung CH, Weissferdt A, Pataer A, ... Heymach JV, Sepesi B</i><br /><AbstractText>Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8<sup>+</sup> T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129 .).</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Genetic association analysis of 77,539 genomes reveals rare disease etiologies.</h4><i>Greene D, Genomics England Research Consortium, Pirri D, Frudd K, ... Mumford A, Turro E</i><br /><AbstractText>The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the \'Rareservoir\', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Optimal dietary patterns for prevention of chronic disease.</h4><i>Wang P, Song M, Eliassen AH, Wang M, ... Tabung FK, Giovannucci EL</i><br /><AbstractText>Multiple dietary patterns have been associated with different diseases; however, their comparability to improve overall health has yet to be determined. Here, in 205,852 healthcare professionals from three US cohorts followed for up to 32 years, we prospectively assessed two mechanism-based diets and six diets based on dietary recommendations in relation to major chronic disease, defined as a composite outcome of incident major cardiovascular disease (CVD), type 2 diabetes and cancer. We demonstrated that adherence to a healthy diet was generally associated with a lower risk of major chronic disease (hazard ratio (HR) comparing the 90th with the 10th percentile of dietary pattern scores = 0.58-0.80). Participants with low insulinemic (HR = 0.58, 95% confidence interval (CI) = 0.57, 0.60), low inflammatory (HR = 0.61, 95% CI = 0.60, 0.63) or diabetes risk-reducing (HR = 0.70, 95% CI = 0.69, 0.72) diet had the largest risk reduction for incident major CVD, type 2 diabetes and cancer as a composite and individually. Similar findings were observed across gender and diverse ethnic groups. Our results suggest that dietary patterns associated with markers of hyperinsulinemia and inflammation and diabetes development may inform on future dietary guidelines for chronic disease prevention.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 13 Mar 2023; epub ahead of print</small></div>

<div><h4>A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.</h4><i>Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, ... Jenq RR, Elinav E</i><br /><AbstractText>Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment (\'high-risk antibiotics\') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 13 Mar 2023; epub ahead of print</small></div>

<div><h4>Challenges and opportunities in NASH drug development.</h4><i>Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N</i><br /><AbstractText>Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD-NASH trials and potential mitigating strategies to move the field forward.</AbstractText><br /><br />© 2023. Springer Nature America, Inc.<br /><br /><small>Nat Med: 09 Mar 2023; epub ahead of print</small></div>

<div><h4>Comparison of two diagnostic intervention packages for community-based active case finding for tuberculosis: an open-label randomized controlled trial.</h4><i>Esmail A, Randall P, Oelofse S, Tomasicchio M, ... Warren RM, Dheda K</i><br /><AbstractText>Two in every five patients with active tuberculosis (TB) remain undiagnosed or unreported. Therefore community-based, active case-finding strategies require urgent implementation. However, whether point-of-care (POC), portable battery-operated, molecular diagnostic tools deployed at a community level, compared with conventionally used POC smear microscopy, can shorten time-to-treatment initiation, thus potentially curtailing transmission, remains unclear. To clarify this issue, we performed an open-label, randomized controlled trial in periurban informal settlements of Cape Town, South Africa, where we TB symptom screened 5,274 individuals using a community-based scalable mobile clinic. Some 584 individuals with HIV infection or symptoms of TB underwent targeted diagnostic screening and were randomized (1:1) to same-day smear microscopy (n = 296) or on-site DNA-based molecular diagnosis (n = 288; GeneXpert). The primary aim was to compare time to TB treatment initiation between the arms. Secondary aims included feasibility and detection of probably infectious people. Of participants who underwent targeted screening, 9.9% (58 of 584) had culture-confirmed TB. Time-to-treatment initiation occurred significantly earlier in the Xpert versus the smear-microscopy arm (8 versus 41 d, P = 0.002). However, overall, Xpert detected only 52% of individuals with culture-positive TB. Notably, Xpert detected almost all of the probably infectious patients compared with smear microscopy (94.1% versus 23.5%, P = <0.001). Xpert was associated with a shorter median time to treatment of probably infectious patients (7 versus 24 d, P = 0.02) and a greater proportion of infectious patients were on treatment at 60 d compared with the probably noninfectious patients (76.5% versus 38.2%, P < 0.01). Overall, a greater proportion of POC Xpert-positive participants were on treatment at 60 d compared with all culture-positive participants (100% versus 46.5%, P < 0.01). These findings challenge the traditional paradigm of a passive case-finding, public health strategy and argues for the implementation of portable DNA-based diagnosis with linkage to care as a community-oriented, transmission-interruption strategy. The study was registered with the South African National Clinical Trials Registry (application ID 4367; DOH-27-0317-5367) and ClinicalTrials.gov (NCT03168945).</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 09 Mar 2023; epub ahead of print</small></div>

<div><h4>Dysbiosis of a microbiota-immune metasystem in critical illness is associated with nosocomial infections.</h4><i>Schlechte J, Zucoloto AZ, Yu IL, Doig CJ, ... McCoy KD, McDonald B</i><br /><AbstractText>Critically ill patients in intensive care units experience profound alterations of their gut microbiota that have been linked to a high risk of hospital-acquired (nosocomial) infections and adverse outcomes through unclear mechanisms. Abundant mouse and limited human data suggest that the gut microbiota can contribute to maintenance of systemic immune homeostasis, and that intestinal dysbiosis may lead to defects in immune defense against infections. Here we use integrated systems-level analyses of fecal microbiota dynamics in rectal swabs and single-cell profiling of systemic immune and inflammatory responses in a prospective longitudinal cohort study of critically ill patients to show that the gut microbiota and systemic immunity function as an integrated metasystem, where intestinal dysbiosis is coupled to impaired host defense and increased frequency of nosocomial infections. Longitudinal microbiota analysis by 16s rRNA gene sequencing of rectal swabs and single-cell profiling of blood using mass cytometry revealed that microbiota and immune dynamics during acute critical illness were highly interconnected and dominated by Enterobacteriaceae enrichment, dysregulated myeloid cell responses and amplified systemic inflammation, with a lesser impact on adaptive mechanisms of host defense. Intestinal Enterobacteriaceae enrichment was coupled with impaired innate antimicrobial effector responses, including hypofunctional and immature neutrophils and was associated with an increased risk of infections by various bacterial and fungal pathogens. Collectively, our findings suggest that dysbiosis of an interconnected metasystem between the gut microbiota and systemic immune response may drive impaired host defense and susceptibility to nosocomial infections in critical illness.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 09 Mar 2023; epub ahead of print</small></div>

<div><h4>Evolution of synchronous female bilateral breast cancers and response to treatment.</h4><i>Hamy AS, Abécassis J, Driouch K, Darrigues L, ... Waterfall JJ, Reyal F</i><br /><AbstractText>Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial.</h4><i>Rosenson RS, Gaudet D, Ballantyne CM, Baum SJ, ... Zhao J, Rader DJ</i><br /><AbstractText>Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg<sup>-1</sup> or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Nat Med: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts.</h4><i>Kundishora AJ, Allington G, McGee S, Mekbib KY, ... Jin SC, Kahle KT</i><br /><AbstractText>Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10<sup>-33</sup>). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.</AbstractText><br /><br />© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 06 Mar 2023; epub ahead of print</small></div>