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Context In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and β-cell function to a greater extent than comparators. Objective Explore changes in biomarkers of β-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. Design Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). Setting Post hoc analysis of 128 sites in 8 countries. Participants A total of 1879 participants with type 2 diabetes. Interventions Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. Main outcomes measures Change in homeostatic model assessment indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. Results At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P <.05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P <.05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C–peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P <.05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. Conclusion In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide. [ABSTRACT FROM AUTHOR]

The Winam Gulf (Kenya) is frequently impaired by cyanobacterial harmful algal blooms (cHABs) due to inadequate wastewater treatment and excess agricultural nutrient input. While phytoplankton in Lake Victoria have been characterized using morphological criteria, our aim is to identify potential toxin‐producing cyanobacteria using molecular approaches. The Gulf was sampled over two successive summer seasons, and 16S and 18S ribosomal RNA gene sequencing was performed. Additionally, key genes involved in production of cyanotoxins were examined by quantitative PCR. Bacterial communities were spatially variable, forming distinct clusters in line with regions of the Gulf. Taxa associated with diazotrophy were dominant near Homa Bay. On the eastern side, samples exhibited elevated cyrA abundances, indicating genetic capability of cylindrospermopsin synthesis. Indeed, near the Nyando River mouth in 2022, cyrA exceeded 10 million copies L−1 where there were more than 6000 Cylindrospermopsis spp. cells mL−1. In contrast, the southwestern region had elevated mcyE gene (microcystin synthesis) detections near Homa Bay where Microcystis and Dolichospermum spp. were observed. These findings show that within a relatively small embayment, composition and toxin synthesis potential of cHABs can vary dramatically. This underscores the need for multifaceted management approaches and frequent cyanotoxin monitoring to reduce human health impacts. [ABSTRACT FROM AUTHOR]

Objective Traditional measures of cognitive abilities most used by neuropsychologists are generally low in ecological validity and only capture a small proportion of the variance of a person's true functional capacity. This study evaluates the association between clinic-based performance and parallel real-world completion of an everyday planning test, the Overnight Trip Task (OTT). Method A cross-sectional cohort of 65 community-dwelling older adults completed a battery of cognitive assessments and two formats of the OTT: the paper-and-pencil clinic OTT, which was completed remotely through video conferencing (Zoom), and the parallel real-world OTT (RW-OTT), which was completed at home between sessions. Both formats required participants to plan for what they would pack and prepare for a hypothetical overnight trip based on a provided story that included rules and embedded contingencies. Results The clinic OTT demonstrated a small-to-moderate relationship with the RW-OTT (r  = 0.35) and no relationship with measures of learning, long delay recall, an executive function composite, and a measure of everyday planning. Hierarchical regressions indicated that the clinic OTT demonstrated incremental validity above an executive function composite measure and global cognition when predicting self-reported everyday functioning and RW-OTT performance. Conclusions The clinic OTT showed only modest association with the RW-OTT and discriminate but not convergent validity was demonstrated. The clinic OTT showed incremental validity when predicting self-reported everyday functioning and RW-OTT performance above more traditional measures. Before the clinic OTT could be considered a reliable and valid clinic-based measure for predicting real-world behavior, additional research would be needed. [ABSTRACT FROM AUTHOR]

Context Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. Objective This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. Methods ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. Results TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA– patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. Conclusion Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity. [ABSTRACT FROM AUTHOR]