Analyses disentangling the role of the gut microbiome in linking lifestyle factors to health outcomes remain limited. Here, using fecal shotgun metagenomics from 6,803 adults in the Japanese 4D cohort, we identified two opposing microbiome-mediated axes linking lifestyle to health and 15 diseases. A health-associated axis enriched in microbial metabolism of dietary components was linked to plant-based, soy and dairy intake. In contrast, a disease-associated axis, enriched in oral-derived bacteria and pathobionts, was linked to refined carbohydrates and sedentary behavior. Starter culture microorganisms used to ferment foods did not show statistically significant mediation of the observed health effects. Alcohol was associated with both health- and disease-oriented mediation patterns involving microbial host-glycan utilization. Microbiome-defined health- and disease-oriented mediator axes were supported by fecal short-chain fatty acids and plasma cytokines from >1,700 individuals, revealing butyrate-associated anti-inflammatory and pro-inflammatory host profiles, respectively. Microbiome-based prediction (MADE) scores captured lifestyle–microbiome–disease mediation patterns and distinguished individual diseases across 13 independent external cohorts from the United States, China, Sweden, Russia and Australia. We identify the gut microbiome as a key mediator linking lifestyle to health and disease, providing a framework for microbiome-based assessment to guide lifestyle interventions for health promotion and disease prevention. Fecal shotgun metagenomics from 6,803 adults in the Japanese 4D cohort and microbiome-based prediction scores validated across 13 independent and geographically diverse cohorts revealed two opposing microbiome-mediated axes linking lifestyle to health and 15 diseases.
El Niño-Southern Oscillation (ENSO) influences the global climate through interconnected atmospheric processes, yet its impact on global and regional temperature-related mortality burden remains unquantified. Here, we integrate global temperature and mortality databases with epidemiological models to assess temperature-related mortality associated with ENSO variability and intensity. During very strong El Niño years, the large amounts of heat released into the atmosphere are associated with an increase in global heat-related mortality of +28.87% (+107,035 annual deaths; 95% eCI: 27,336 to 176,312), and a decrease in global cold-related mortality of −3.70% (−112,681 annual deaths; 95% eCI: -207,619 to -22,203). Increase in heat-related mortality was concentrated in low and medium HDI countries, which accounted for 67.65% of the global increase, with the largest increase in medium HDI countries (+61,863 annual deaths; 95% eCI: 19,939 to 105,888), while point estimates of the combined heat and cold burden suggest a shift of the total burden from high toward lower HDI countries. In a context of continuously warming temperatures, our results indicate that forthcoming El Niño events have the potential to represent new public health challenges, underscoring the need for climate-informed preparedness actions. Epidemiological estimates suggest that global heat-related mortality increased by 29% during very strong El Niño years, with the greatest burdens occurring in low- and medium- Human Development Index regions.
Resectable non-small cell lung cancer (NSCLC) carries a high risk of postoperative recurrence, underscoring the need for effective perioperative therapies. This nonrandomized, noncomparative phase 2 trial evaluated neoadjuvant ivonescimab monotherapy (cohort 1) or in combination with chemotherapy (cohort 2), followed by surgery and adjuvant ivonescimab. In cohort 2, the major pathological response (MPR) rate was 70.1% (47/67; 95% confidence interval (CI) = 57.7–80.7); the lower bound of the 80% two-sided CI exceeded the historical control rate of 41% and the primary endpoint was met. The MPR rate in cohort 1 was 60.0% (6/10; 95% CI = 26.2–87.8). Among patients who achieved MPR, 83.3% (5/6) in cohort 1 and 97.9% (46/47) in cohort 2 had residual viable tumor (RVT) of ≤5%, respectively. Grade 3 or higher treatment-related adverse events (AEs) occurred in 36.4% (4/11) patients in cohort 1 and 30.4% (24/79) of those in cohort 2, with no grade 3 or higher hemorrhage or treatment-related death. Treatment-related surgery delay occurred in one (1.3%) patient. Surgery-related AEs related to ivonescimab occurred in 10.0% (1/10) and 10.4% (7/67) patients in the two cohorts, respectively, with no grade 3 or higher events reported. These data support perioperative ivonescimab with or without chemotherapy as a promising strategy for resectable NSCLC. ClinicalTrials.gov identifier: NCT05247684 . In a nonrandomized phase 2 trial, patients with resectable non-small cell lung cancer received perioperative ivonescimab as monotherapy or with chemotherapy, leading to encouraging pathological response rates in both cohorts, and sustained circulating tumor DNA negativity throughout neoadjuvant therapy may be predictive of response.
