In this issue, Sato and colleagues tested the ability of isoform-specific tau species in cerebrospinal fluid (CSF) to distinguish different subtypes of primary tauopathies. The left and right sides of the tree portray the pathological and healthy brain, respectively, populated with leaves of tau isoforms, with the falling leaves being isoforms represented in the CSF.

See Kanta Horie et al.

In this issue, Langenberg and colleagues reveal the genetic architecture that underpins individualized metabolic profiles and their relationship with clinical phenotypes. The tattoos of metabolic pathways on the cover reflect the chemical individuality of the person, with the base codes in the background representing the genetics that underlie the metabolic phenotypes.

See Langenberg et al.

In this issue, five Burden of Proof studies from the Institute for Health Metrics and Evaluation present a new method for assessing the cumulative strength of available evidence for risk factors and associated health outcomes. Together, these papers describe the methodology and demonstrate the utility of the approach with exemplars over which the burden of proof spans a range of certainty. The magnifying glass in the cover image represents the burden of proof risk function, which enables a closer view of risk factors and the evidence for associated health outcomes.

See Zheng et al.

Two papers in this issue from Bork et al. and Segata et al., respectively, explore factors of donor and recipient microbiomes that drive engraftment of fecal microbiota transplantation (FMT) and the effects of this dynamic process on clinical outcomes. Donor and recipient gastrointestinal tracts and their microbiomes are represented on the cover as converging pipes, demonstrating the interplay between the microbial communities after FMT, described in Bork et al.

See Bork et al.

In this issue, Subbiah and colleagues report findings from ARROW, a phase 1/2 clinical trial testing pralsetinib, a tumor-agnostic inhibitor of the receptor tyrosine kinase RET, in a range of solid tumors. The cover image depicts a diverse group of patients, each with different cancers harbouring RET fusions, all treated with pralsetinib.

See Subbiah et al.

Two papers by Saria and colleagues in this issue report results from the prospective evaluation of deployment of a machine learning–based early warning system for sepsis in five hospitals. The cover depicts elements of the integrated artificial intelligence platform that expands the capacity of healthcare providers to visualize and interpret signs of deterioration associated with sepsis, leading to opportunities for early intervention and improved patient outcomes.

See Saria and colleagues and Saria and colleagues

In this issue, Bruel et al. demonstrate substantial differences in the sensitivity of the SARS-CoV-2 Delta variant and Omicron sublineages BA.1 and BA.2 to neutralization by nine therapeutic monoclonal antibodies. The cover combines an image of SARS-CoV-2-infected cells fusing with neighboring cells to form syncytia with a view of Earth, reflective of the ongoing global impact of the pandemic.

See Bruel et al.

Shaked et al. applied a polygenic risk score for type 2 diabetes to liver and kidney transplant donors and recipients with the aim of identifying genetic associations with the development of post-transplantation diabetes mellitus. The cover is illustrative of genetic puzzle pieces in both the donor and the recipient, which can be leveraged to inform and develop personalized treatment strategies and to optimize donor–recipient matching.

See Shaked et al.

This special Focus issue presents an overview of the most promising developments in cancer research, with an eye toward delivering research and care that is innovative, equitable, sustainable and patient-focused. The cover presents an artistic rendition of the study by Seliger and colleagues, in this issue, showing an increased risk of death by suicide in patients with cancer and underscoring the need for comprehensive psycho-oncological therapy during routine clinical practice to improve the quality of life of such patients.

See Focus

Local communities protect the Amazon rainforest from illegal logging and mining, but this is threatened by a lack of local healthcare. Journalist Sofia Moutinho traveled with a medical team who delivered vaccines for COVID-19 and other supplies during a monthlong boat trip along the Amazon River.

See News Feature

Fowler et. al report their primary analysis of the ELARA phase 2 trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, that showed a robust response and manageable safety profile in heavily pre-treated patients with relapsed/refractory follicular lymphoma. Captured in a moment of suspense, the illustrated cover casts a retro space-age mood over the scene as a tisagenlecleucel CAR T cell recognizes and targets a CD19-expressing follicular lymphoma within the tumor microenvironment, highlighting the selective and specific mechanism of this novel cellular therapy.

See Fowler et al.

Lipoprotein ‘a’ [Lp(a)] is a causal genetic risk factor for atherosclerotic cardiovascular disease. Koren et al. describe the early development of olpasiran, a hepatocyte-targeted small interfering RNA that potently and durably reduces plasma Lp(a) concentrations in humans. Lp(a) particles are composed of a lipid-rich core (yellow sphere) associated with a protein complex that consists of apolipoprotein(a) (apo(a), shown as a coiled structure with conserved kringle repeats in different colors) covalently bound to apolipoprotein B-100. The number of apo(a) kringle repeats is genetically defined, varies widely between individuals, and determines plasma concentrations of Lp(a).

See Koren et al.